Ester Derivatives of Bimatoprost Compositions and Methods

ABSTRACT

Provided herein, inter alia, are prodrugs of bimatoprost, methods of using the same and compositions including the same.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Ser.No. 61,442,400, filed Feb. 14, 2011, the disclosure of which is herebyincorporated in its entirety herein by reference and for all purposes.

FIELD OF THE INVENTION

The present invention is directed to, inter alia, prodrugs ofbimatoprost, formulations containing prodrugs of bimatoprost, and usesof bimatoprost prodrugs.

BACKGROUND OF THE INVENTION

Bimatoprost isomer[(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((S,E)-3-hydroxy-5-phenylpent-1-enyl)cyclopentyl)-N-ethylhept-5-enamide](sold under the name Lumigan® by Allergen, Inc., Irvine, Calif.), wasinitially developed for the treatment of a variety of diseases ordisorders, including ocular hypertension and glaucoma. See U.S. Pat.Nos. 5,607,978, 5,688,819, 6,403,649, 8,017,655.

It has been observed that administration of bimatoprost results inhypertrichosis (i.e., increased hair growth) in treated regions. Indeed,results of administration of bimatoprost include altereddifferentiation, number, length, thickness, curvature and pigmentation.

Accordingly, there is a need to provide derivatives of bimatoprost,including prodrugs, which provide efficacy in the treatment of a varietyof diseases or disorders, such as lowering intraocular pressure, hairloss, inflammatory diseases and disorders of the skin, and for thereduction of local adipose deposits. Provided herein are solutions tothese and other needs in the art.

The entire contents of each patent or publication cited herein areincorporated by reference in its entirety for all purposes.

BRIEF SUMMARY OF THE INVENTION

In a first aspect, there is provided a compound with the structure ofFormula (I),

or derivative, isomer, or enantiomer thereof. R¹ is hydrogen orR^(1a)C(O)—. R² is hydrogen or R^(2a)C(O)—. R³ is hydrogen orR^(3a)C(O)—. R^(1a), R^(2a) and R^(3a) are independently substituted orunsubstituted C₁-C₁₀ alkyl, substituted or unsubstituted C₃-C₈cycloalkyl, or substituted or unsubstituted aryl. R⁴ and R⁵ areindependently hydrogen, substituted or unsubstituted C₁-C₁₀ alkyl, orsubstituted or unsubstituted C₃-C₈ cycloalkyl. In some embodiments, atleast one of R¹, R² and R³ is not hydrogen.

In another aspect, there is provided a pharmaceutical composition. Thepharmaceutical composition includes a pharmaceutically acceptableexcipient and a compound with the structure of Formula (I) orderivative, isomer, or enantiomer thereof. R¹ is hydrogen orR^(1a)C(O)—. R² is hydrogen or R^(2a)C(O)—. R³ is hydrogen orR^(3a)C(O)—. R^(1a), R^(2a) and R^(3a) are independently substituted orunsubstituted C₁-C₁₀ alkyl, substituted or unsubstituted C₃-C₈cycloalkyl, or substituted or unsubstituted aryl. R⁴ and R⁵ areindependently hydrogen, substituted or unsubstituted C₁-C₁₀ alkyl, orsubstituted or unsubstituted C₃-C₈ cycloalkyl. In some embodiments, atleast one of R¹, R² and R³ is not hydrogen.

In another aspect, there is provided a method for inducing hair growth.The method includes administering to a subject in need thereof atherapeutically effective amount of a compound provided herein (e.g., acompound with structure of Formula (I), (II), (III), (IV), (IIa), (IIb),(IIc), (IIIa), (IIIb), (IIIc), (IIId), (IVa), (IVb), or (IVc) orderivative, isomer or enantiomer thereof and including embodimentsthereof). The compound may be provided as part of a pharmaceuticalcomposition as described herein.

In another aspect, there is provided a method for lowering intraocularpressure. The method includes administering to a subject in need thereofa therapeutically effective amount of a compound provided herein (e.g.,a compound with structure of Formula (I), (II), (III), (IV), (IIa),(IIb), (IIc), (IIIa), (IIIb), (IIIc), (IIId), (IVa), (IVb), or (IVc) orderivative, isomer or enantiomer thereof and including embodimentsthereof). The compound may be provided as part of a pharmaceuticalcomposition as described herein.

In another aspect, there is provided a method of treating glaucoma Themethod includes administering to a subject in need thereof atherapeutically effective amount of a compound provided herein (e.g., acompound with structure of Formula (I), (II), (III), (IV), (IIa), (IIb),(IIc), (IIIa), (IIIb), (IIIc), (IIId), (IVa), (IVb), or (IVc) orderivative, isomer or enantiomer thereof and including embodimentsthereof). The compound may be provided as part of a pharmaceuticalcomposition as described herein.

In another aspect, there is provided a method for treating aninflammatory skin disease or disorder. The method includes administeringto a subject in need thereof a therapeutically effective amount of acompound provided herein (e.g., a compound with structure of Formula(I), (II), (III), (IV), (IIa), (IIb), (IIc), (IIIa), (IIIb), (IIIc),(IIId), (IVa), (IVb), or (IVc) or derivative, isomer or enantiomerthereof and including embodiments thereof). The compound may be providedas part of a pharmaceutical composition as described herein.

In another aspect, there is provided a method for reducing adiposetissue (e.g., local adipose deposits). The method includes administeringto a subject in need thereof a therapeutically effective amount of acompound provided herein (e.g., a compound with structure of Formula(I), (II), (III), (IV), (IIa), (IIb), (IIc), (IIIa), (IIIb), (IIIc),(IIId), (IVa), (IVb), or (IVc) or derivative, isomer or enantiomerthereof and including embodiments thereof). The compound may be providedas part of a pharmaceutical composition as described herein.

Embodiments of the invention include the following:

Embodiment 1. A compound having the formula:

or derivative, isomer, or enantiomer thereof;whereinR¹ is hydrogen or R^(1a)C(O)—;R² is hydrogen or R^(2a)C(O)—;R³ is hydrogen or R^(3a)C(O)—;R^(1a), R^(2a) and R^(3a) are independently substituted or unsubstitutedC₁-C₁₀ alkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, orsubstituted or unsubstituted aryl; andR⁴ and R⁵ are independently hydrogen, substituted or unsubstitutedC₁-C₁₀ alkyl, or substituted or unsubstituted C₃-C₈ cycloalkyl;provided, however, that at least one of R¹, R² and R³ is not hydrogen.

Embodiment 2. The compound of embodiment 1, wherein R^(1a), R^(2a) andR^(3a) are independently substituted or unsubstituted C₁-C₆ alkyl.

Embodiment 3. The compound of embodiment 2, wherein R^(1a), R^(2a) andR^(3a) are independently substituted or unsubstituted C₁-C₃ alkyl.

Embodiment 4. The compound of embodiment 3, wherein R^(1a), R^(2a) andR^(3a) are independently substituted or unsubstituted C₁ alkyl.

Embodiment 5. The compound of any one of embodiments 1 or 4, whereinR^(1a), R^(2a) and R^(3a) are independently methyl.

Embodiment 6. The compound of embodiment 1, wherein R^(1a), R^(2a) andR^(3a) are independently substituted or unsubstituted C₃-C₈ cycloalkyl.

Embodiment 7. The compound of any one of embodiments 1 or 6, whereinR^(1a), R^(2a) and R^(3a) are independently unsubstituted C₃-C₈cycloalkyl.

Embodiment 8. The compound of embodiment 1, wherein R^(1a), R^(2a) andR^(3a) are independently substituted or unsubstituted aryl.

Embodiment 9. The compound of embodiment 8, wherein R^(1a), R^(2a) andR^(3a) are independently aryl.

Embodiment 10. The compound of embodiment 1, wherein R^(1a), R^(2a) andR^(3a) are independently phenyl.

Embodiment 11. The compound of any one of embodiments 1 to 10, whereinR⁴ is substituted or unsubstituted C₁-C₁₀ alkyl, or substituted orunsubstituted C₃-C₈ cycloalkyl.

Embodiment 12. The compound of any one of embodiments 1 to 11, whereinR⁴ is substituted or unsubstituted C₁-C₆ alkyl.

Embodiment 13. The compound of any one of embodiments 1 to 12, whereinR⁴ is substituted or unsubstituted C₁-C₃ alkyl.

Embodiment 14. The compound of any one of embodiments 1 to 13, whereinR⁴ is substituted or unsubstituted C₂ alkyl.

Embodiment 15. The compound of any one of embodiments 1 to 14, whereinR⁴ is ethyl.

Embodiment 16. The compound of any one of embodiments 1 to 11, whereinR⁴ is substituted or unsubstituted C₃-C₈ cycloalkyl.

Embodiment 17. The compound of any one of embodiments 1 to 16, whereinR⁵ is hydrogen.

Embodiment 18. The compound of embodiment 1 having the formula:

Embodiment 19. The compound of embodiment 1 having the formula:

Embodiment 20. The compound of embodiment 1 having the formula:

Embodiment 21. A pharmaceutical composition comprising apharmaceutically acceptable excipient and a compound having the formula:

or derivative, isomer, or enantiomer thereof;whereinR¹ is hydrogen or R^(1a)C(O)—;R² is hydrogen or R^(2a)C(O)—;R³ is hydrogen or R^(3a)C(O)—;R^(1a), R^(2a) and R^(3a) are independently substituted or unsubstitutedC₁-C₁₀ alkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, orsubstituted or unsubstituted aryl; andR⁴ and R⁵ are independently hydrogen, substituted or unsubstitutedC₁-C₁₀ alkyl, or substituted or unsubstituted C₃-C₈ cycloalkyl;provided, however, that at least one of R¹, R² and R³ is not hydrogen.

Embodiment 22. The pharmaceutical composition of embodiment 21, whereinsaid compound has the formula:

Embodiment 23. The pharmaceutical composition of embodiment 22, whereinsaid compound is the compound of Formula (IVb).

Embodiment 24. The pharmaceutical composition of any one of embodiments21 to 23, wherein said pharmaceutical composition is a solution,emulsion, gel or foam.

Embodiment 25. The pharmaceutical composition of any one of embodiments21 to 23, wherein said pharmaceutical composition is a topicalpharmaceutical composition.

Embodiment 26. The pharmaceutical composition of embodiment 25, whereinsaid pharmaceutical composition is a topical epidermal pharmaceuticalcomposition.

Embodiment 27. The pharmaceutical composition of embodiment 21, whereinsaid compound is the compound of any one of embodiments 2 to 17.

Embodiment 28. A method for inducing piliation or hair growth in a humancomprising administering to a subject in need thereof a therapeuticallyeffective amount of a compound having the formula:

or derivative, isomer, or enantiomer thereof;whereinR¹ is hydrogen or R^(1a)C(O)—;R² is hydrogen or R^(2a)C(O)—;R³ is hydrogen or R^(3a)C(O)—;R^(1a), R^(2a) and R^(3a) are independently substituted or unsubstitutedC₁-C₁₀ alkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, orsubstituted or unsubstituted aryl; andR⁴ and R⁵ are independently hydrogen, substituted or unsubstitutedC₁-C₁₀ alkyl, or substituted or unsubstituted C₃-C₈ cycloalkyl;provided, however, that at least one of R¹, R² and R³ is not hydrogen;thereby inducing hair growth.

Embodiment 29. The method of embodiment 28, wherein said subject suffersfrom alopecia.

Embodiment 30. The method of embodiment 28, wherein said subject is inneed of piliation of the cilia, the supercilia, scalp pili, or bodypili.

Embodiment 31. The method of embodiment 28, wherein said administeringis topical administering.

Embodiment 32. The method of embodiment 31, wherein said administeringis topical epidermal administering.

Embodiment 33. The method of embodiment 28, wherein R^(1a), R^(2a) andR^(3a) are independently substituted or unsubstituted C₁-C₆ alkyl.

Embodiment 34. The method of embodiment 33, wherein R^(1a), R^(2a) andR^(3a) are independently substituted or unsubstituted C₁-C₃ alkyl.

Embodiment 35. The method of embodiment 34, wherein R^(1a), R^(2a) andR^(3a) are independently substituted or unsubstituted C₁ alkyl.

Embodiment 36. The method of embodiment 35, wherein R^(1a), R^(2a) andR^(3a) are independently methyl.

Embodiment 37. The method of embodiment 28, wherein R^(1a), R^(2a) andR^(3a) are independently substituted or unsubstituted C₃-C₈ cycloalkyl.

Embodiment 38. The method of embodiment 37, wherein R^(1a), R^(2a) andR^(3a) are independently unsubstituted C₃-C₈ cycloalkyl.

Embodiment 39. The method of embodiment 28, wherein R^(1a), R^(2a) andR^(3a) are independently substituted or unsubstituted aryl.

Embodiment 40. The method of embodiment 39, wherein R^(1a), R^(2a) andR^(3a) are independently aryl.

Embodiment 41. The method of embodiment 40, wherein R^(1a), R^(2a) andR^(3a) are independently phenyl.

Embodiment 42. The method of any one of embodiments 28 to 41, wherein R⁴is substituted or unsubstituted C₁-C₁₀ alkyl, or substituted orunsubstituted C₃-C₈ cycloalkyl.

Embodiment 43. The method of any one of embodiments 28 to 42, wherein R⁴is substituted or unsubstituted C₁-C₆ alkyl.

Embodiment 44. The method of any one of embodiments 28 to 43, wherein R⁴is substituted or unsubstituted C₁-C₃ alkyl.

Embodiment 45. The method of any one of embodiments 28 to 44, wherein R⁴is substituted or unsubstituted C₂ alkyl.

Embodiment 46. The method of any one of embodiments 28 to 45, wherein R⁴is ethyl.

Embodiment 47. The method of any one of embodiments 28 to 42, wherein R⁴is substituted or unsubstituted C₃-C₈ cycloalkyl.

Embodiment 48. The method of any one of embodiments 28 to 47, wherein R⁵is hydrogen.

Embodiment 49. The method of embodiment 28, wherein said compound is

Embodiment 50. The method of embodiment 49, wherein said compound is thecompound of Formula (IVb).

Embodiment 51. The method of any one of embodiments 28 to 50, whereinsaid composition is a solution, emulsion, gel or foam.

Embodiment 52. The method of any one of embodiments 28 to 51, whereinsaid administering is topical palpebra administering, topicalsupercilium administering, topical scalp administering, or topical bodyadministering.

Embodiment 53. The method of any one of embodiments 28 to 52, whereinsaid administering is topical scalp administering, and said compositionis a foam or gel.

Embodiment 54. The method of any one of embodiments 28 to 53, whereinsaid administering is topical palpebra administering, and saidcomposition is administered by an application brush disposed within aunit dose vial.

Embodiment 55. A method for lowering intraocular pressure comprisingadministering to a subject in need thereof a therapeutically effectiveamount of a compound with structure of Formula (I):

or derivative, isomer, or enantiomer thereof;whereinR¹ is hydrogen or R^(1a)C(O)—;R² is hydrogen or R^(2a)C(O)—;R³ is hydrogen or R^(3a)C(O)—;R^(1a), R^(2a) and R^(3a) are independently substituted or unsubstitutedC₁-C₁₀ alkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, orsubstituted or unsubstituted aryl; andR⁴ and R⁵ are independently hydrogen, substituted or unsubstitutedC₁-C₁₀ alkyl, or substituted or unsubstituted C₃-C₈ cycloalkyl;provided, however, that at least one of R¹, R² and R³ is not hydrogen;thereby lowering intraocular pressure.

Embodiment 56. The method of embodiment 55, wherein said subject suffersfrom elevated intraocular pressure or glaucoma.

Embodiment 57. The method of embodiment 56, wherein said subject suffersfrom glaucoma.

Embodiment 58. The method of any one of embodiments 55 to 58, whereinsaid compound is the compound of any one of embodiments 2 to 20.

Embodiment 59. A method for treating an inflammatory skin disease ordisorder comprising administering to a subject in need thereof atherapeutically effective amount of a compound with structure of Formula(I):

or derivative, isomer, or enantiomer thereof;whereinR¹ is hydrogen or R^(1a)C(O)—;R² is hydrogen or R^(2a)C(O)—;R³ is hydrogen or R^(3a)C(O)—;R^(1a), R^(2a) and R^(3a) are independently substituted or unsubstitutedC₁-C₁₀ alkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, orsubstituted or unsubstituted aryl; andR⁴ and R⁵ are independently hydrogen, substituted or unsubstitutedC₁-C₁₀ alkyl, or substituted or unsubstituted C₃-C₈ cycloalkyl;provided, however, that at least one of R¹, R² and R³ is not hydrogen;thereby treating an inflammatory skin disease or disorder.

Embodiment 60. The method of embodiment 59, wherein said subject suffersfrom rosacea or redness from rosacea.

Embodiment 61. The method of any one of embodiments 59 to 60, whereinsaid compound is the compound of any one of embodiments 2 to 20.

Embodiment 62. A method for reducing local adipose deposits comprisingadministering to a subject in need thereof a therapeutically effectiveamount of a compound with structure of Formula (I),

or derivative, isomer, or enantiomer thereof;whereinR¹ is hydrogen or R^(1a)C(O)—;R² is hydrogen or R^(2a)C(O)—;R³ is hydrogen or R^(3a)C(O)—;R^(1a), R^(2a) and R^(3a) are independently substituted or unsubstitutedC₁-C₁₀ alkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, orsubstituted or unsubstituted aryl; andR⁴ and R⁵ are independently hydrogen, substituted or unsubstitutedC₁-C₁₀ alkyl, or substituted or unsubstituted C₃-C₈ cycloalkyl;provided, however, that at least one of R¹, R² and R³ is not hydrogen;thereby reducing local adipose deposit.

Embodiment 63. The method of embodiment 62, wherein said compound is thecompound of any one of embodiments 2 to 20.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. FIG. 1A depicts a histogram of relative concentration of CmpdIVa over time as a function of temperature and pH. Group name “Time 0”refers to the start of the experiment. Group names “25 C,” “40 C” and“60 C” refer to incubation temperatures. For each group, the pH (left toright) was pH 4 (open), pH 5 (horizontal stripes), pH 6 (diagonalstripes lower left to upper right), and pH 7 (diagonal stripes upperleft to lower right). FIG. 1B depicts a histogram of the formation ofbimatoprost as a function of pH and temperature after 80-days. For eachgroup of FIG. 1B, the temperature (left to right) was 40° C. (open) and60° C. (horizontal stripes). See Example 1.

FIG. 2. FIG. 2A depicts a histogram of relative concentration of CmpdIVb over time as a function of temperature and pH. Group names are asgiven for FIG. 1A. For each group, the pH (left to right) was pH 4(open), pH 5 (horizontal stripes), pH 6 (diagonal stripes lower left toupper right), and pH 7 (diagonal stripes upper left to lower right).FIG. 2B depicts a histogram of the formation of bimatoprost as afunction of pH and temperature after 80-days. For each group of FIG. 2B,the temperature (left to right) was 40° C. (open) and 60° C. (horizontalstripes). See Example 1.

FIG. 3. FIG. 3A depicts a histogram of relative concentration of CmpdIIIb over time as a function of temperature and pH. Group names are asgiven for FIG. 1A. For each group, the pH (left to right) was pH 4(open), pH 5 (horizontal stripes), pH 6 (diagonal stripes lower left toupper right), and pH 7 (diagonal stripes upper left to lower right).FIG. 3B depicts a histogram of the formation of bimatoprost as afunction of pH and temperature after 80-days. For each group of FIG. 3B,the temperature (left to right) was 40° C. (open) and 60° C. (horizontalstripes). See Example 1.

FIG. 4. FIG. 4A depicts a histogram of the results of the day of onsetof hair growth in piliation studies in mice. See Example 12. Legend: (A)vehicle; (B) 0.03% bimatoprost; (C) 0.03% Cmpd IIc; (D) 0.03% Cmpd IIa;and (E) 0.03% Cmpd IIIa. FIG. 4B depicts a histogram of thecorresponding day of full hair growth. Legend: as in FIG. 4A.

FIG. 5. FIG. 5A depicts a histogram of the results of the day of onsetof hair growth in piliation studies in mice. See Example 12. Legend: (A)vehicle; (B) 0.03% bimatoprost; (C) 0.03% Cmpd IIId; and (D) 0.03% CmpdIVa. FIG. 5B depicts a histogram of the corresponding day of full hairgrowth. Legend: as in FIG. 5A.

FIG. 6. FIG. 6A depicts a histogram of the results of the day of onsetof hair growth in piliation studies in mice. See Example 12. Legend: (A)vehicle; (B) 0.03% bimatoprost; (C) 0.03% Cmpd IVb; (D) 0.03% Cmpd IIIb;(E) 0.03% Cmpd IVc; and (F) 0.03% Cmpd IIIc. FIG. 6B depicts a histogramof the corresponding day of full hair growth. Legend: as in FIG. 6A.

FIG. 7. FIG. 7A depicts a histogram of the results of the day of onsetof hair growth in piliation studies in mice. See Example 12. Legend: (A)vehicle (Formulation A); (B) 0.03% bimatoprost; (C) 0.03% Cmpd IVa; (D)0.03% Cmpd IIIb; and (E) 0.03% Cmpd IVb. FIG. 7B depicts a histogram ofthe corresponding day of full hair growth. Legend: as in FIG. 7A.

FIG. 8. FIG. 8A depicts a histogram of the results of the day of onsetof hair growth in piliation studies in mice. See Example 12. Legend: (A)vehicle; (B) 0.03% bimatoprost; (C) 0.03% Cmpd IIIb; and (D) 0.03% CmpdIVb. FIG. 8B depicts a histogram of the corresponding day of full hairgrowth. Legend: as in FIG. 8A.

FIG. 9. FIG. 9A depicts a histogram of the results of the day of onsetof hair growth in piliation studies in mice. See Example 12. Legend: (A)vehicle; (B) 0.3% bimatoprost; (C) 0.1% bimatoprost; (D) 0.03%bimatoprost; and (E) 0.03% Cmpd IVa. FIG. 9B depicts a histogram of thecorresponding day of full hair growth. Legend: as in FIG. 9A.

FIG. 10. FIGS. 10A-10E depict photomicrographs of vehicle, 0.03%bimatoprost, 0.03% Cmpd IVa, 0.03% Cmpd IIIb, and 0.03% Cmpd IVb,respectively, obtained for pathology assessment of a mouse hair regrowthmodel. See Example 13.

FIG. 11. FIG. 11A depicts mean concentration of bimatoprost and CmpdsIVa, IIIb and IVb in the skin in a pharmacokinetic assessment of a mousehair regrowth model. Identification of test compound is provided at the24-hr mark of day-1, in the order (top to bottom), bimatoprost, CmpdIVb, Cmpd IVa, and Cmpd IIIb. See Example 14. FIG. 11B depicts meanconcentration of bimatoprost at the equivalent time points.

FIG. 12. FIG. 12 depicts the time course of formation of bimatoprostfrom Cmpd IVa and Cmpd IVb as determined in human cadaver skin. SeeExample 15. Legend: Cmpd IVa (diamonds); Cmpd IVb (triangles).

FIG. 13. FIG. 13A depicts a histogram of the cumulative total amount inreceptor solution of the indicated compound in a Franz diffusionchamber. See Example 16. For each group, the order (left to right) ofentries is bimatoprost (open), Cmpd IVa (horizontal stripes), Cmpd IIIb(diagonal stripes lower left to upper right) and Cmpd IVb (diagonalstripes upper left to lower right). FIG. 13B depicts the time course ofpenetration flux of the indicated compound.

FIG. 14. FIGS. 14A-14C depict histograms of the time course ofappearance of bimatoprost as detected in the receptor chamber solutionof the Franz diffusion chamber. See Example 16. Compounds are recited inorder left to right: A (bimatoprost); B (Cmpd IVa); C (Cmpd IIIb); and D(Cmpd IVb). Timing: FIG. 14A (6 hr); FIG. 14B (24 hr); FIG. 14C (48 hr).Legend: Dosed (open); metabolite (horizontal stripes).

FIG. 15. FIG. 15A depicts a histogram of the retained amount ofindicated compound in the skin (SC/Epi/Der) in a ex vivo human skinassay. FIG. 15B depicts a histogram of skin retention per agent in thedermis. See Example 16. Legend: “Dosed” (open); “Metabolite” (horizontalstripes). “Dosed” refers to administered compound. “Metabolite” refersto compound resulting from reaction in assay (e.g., hydrolysis).

FIG. 16. FIG. 16A depicts a typical explanted sample of mouse skin forstudies wherein Cmpd IVa was applied via dermal administration. SeeExample 18. FIG. 16B depicts the result of MALDI-MS imaging. Theintensity of each pixel within FIG. 16B reflects the concentration ofCmpd IVa at the corresponding point in the image depicted in FIG. 16A.The white circle within FIG. 16B indicates the position of the MALDI-MSanalysis depicted in FIG. 16C. FIG. 16C depicts a representative massspectrum of the region indicated by the white circle in FIG. 16B.X-axis: m/z; Y-axis: mass intensity. Each pixel of the image of FIG. 16Bhas an associated mass spectrum, providing the amounts of bimatoprost orother administered compound or metabolite thereof.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

Unless otherwise stated, the following terms used in the specificationand claims are defined for the purposes of this application and have thefollowing meaning. The abbreviations used herein have their conventionalmeaning within the chemical and biological arts. The chemical structuresand formulae set forth herein are constructed according to the standardrules of chemical valency known in the chemical arts.

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight (i.e. unbranched) or branched chain,or combination thereof, which may be fully saturated (referred to hereinas a “saturated alkyl”), mono- or polyunsaturated and can include di-and multivalent radicals, having the number of carbon atoms designated(i.e. C₁-C₁₀ means one to ten carbons). In some embodiments, all alkylsset forth as a substituent of the compounds provided herein aresaturated alkyls. Examples of saturated hydrocarbon radicals include,but are not limited to, groups such as methyl, ethyl, n-propyl,isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, homologs and isomersof, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Anunsaturated alkyl group is one having one or more double bonds or triplebonds. n “alkoxy” is an alkyl attached to the remainder of the moleculevia an oxygen linker (—O—). An “alkylthio” is an alkyl attached to theremainder of the molecule via an sulfur linker (—S—). A “haloalkoxy” isan alkoxy substituted with a halogen. When the halogen is a fluoro, itis referred to herein as a “fluoroalkoxy.” The term “alkyl” includessaturated alkyl, alkenyl and alkynyl. A saturated alkyl may have from 1to 10 or 1 to 6 carbon atoms. The term “alkenyl” by itself or as part ofanother substituent, means, unless otherwise stated, a straight (i.e.unbranched) or branched hydrocarbon chain (e.g., two to ten, or two tosix carbon atoms) having one or more double bonds. Examples ofunsaturated alkyl groups include, but are not limited to, vinyl,2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl,3-(1,4-pentadienyl), and the like. The term “alkynyl” by itself or aspart of another substituent, means, unless otherwise stated, a straight(i.e. unbranched) or branched hydrocarbon chain (e.g., two to ten or twoto six carbon atoms) having one or more triple bonds. Examples ofalkynyl groups include, but are not limited to, ethynyl, 1- and3-propynyl, 3-butynyl, and the like.

“Aminocarbonyl” means a —CONRR′ radical where R is independentlyhydrogen, unsubstituted alkyl, or alkyl substituted with a substituentgroup and R′ is hydrogen, unsubstituted alkyl, unsubstituted cycloalkyl,unsubstituted cycloalkylalkyl, unsubstituted aryl, unsubstitutedaralkyl, unsubstituted heteroaryl, unsubstituted heteroaralkyl,unsubstituted heterocycloalkyl, unsubstituted heterocyclylalkyl, oralkyl substituted with a substituent group, each as defined herein andwherein the aryl, heteroaryl, or heterocyclyl ring either alone or partof another group e.g., aralkyl, is optionally substituted with one, two,or three substituent group(s). Likewise, “aminosulfonyl” means a—SO₂NRR′ radical where R and R′ are as defined for aminocarbonyl.

The term “alkylene”, “alkenylene, and “alkynylene” by itself or as partof another substituent means a divalent radical derived from an alkyl,alkenyl, or alkynyl as exemplified, but not limited, by methylene,ethylene, —CH₂CH₂CH₂CH₂—, vinylene and the like.

The term “amino” as used herein means a —NH₂. The term “carboxy” as usedherein means —COOH (including pharmaceutically acceptable saltsthereof).

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain orcombinations thereof, consisting of at least one carbon atom and atleast one heteroatom selected from the group consisting of O, N, P, Sior S, and wherein the nitrogen and sulfur atoms may optionally beoxidized and the nitrogen heteroatom may optionally be quaternized. Theheteroatom(s) O, N, P and S and Si may be placed at any interiorposition of the heteroalkyl group or at the position at which the alkylgroup is attached to the remainder of the molecule. Examples include,but are not limited to, —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃,—CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂, —S(O)—CH₃,—CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃, —CH₂—CH═N—OCH₃,—CH═CH—N(CH₃)—CH₃, —O—CH₃, —O—CH₂—CH₃, and —CN. Up to two heteroatomsmay be consecutive, such as, for example, —CH₂—NH—OCH₃. Similarly, theterm “heteroalkylene” by itself or as part of another substituent meansa divalent radical derived from heteroalkyl, as exemplified, but notlimited by, —CH₂—CH₂—S—CH₂—CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. Forheteroalkylene groups, heteroatoms can also occupy either or both of thechain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino,alkylenediamino, and the like). As described above, heteroalkyl groups,as used herein, include those groups that are attached to the remainderof the molecule through a heteroatom

The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or incombination with other terms, represent, unless otherwise stated,non-aromatic cyclic versions of “alkyl” and “heteroalkyl”, respectively(e.g., having 4 to 8 ring atoms). Additionally, for heterocycloalkyl, aheteroatom can occupy the position at which the heterocycle is attachedto the remainder of the molecule. Heterocycloalkyls may include one ortwo ring heteroatoms selected from N, O, or S(O)_(n′), where n′ is aninteger from 0 to 2, the remaining ring atoms being carbon. Theheterocycloalkyl or cycloalkyl ring is optionally fused to one or morearyl or heteroaryl rings as defined herein (e.g., where the aryl andheteroaryl rings are monocyclic). The heterocycloalkyl or cycloalkylring fused to monocyclic aryl or heteroaryl ring may be referred to inthis application as “bicyclic heterocycloalkyl” ring or a “bicycliccycloalkyl” ring. Additionally, one or two ring carbon atoms in theheterocycloalkyl ring can optionally be replaced by a —CO— group. Morespecifically the term heterocycloalkyl includes, but is not limited to,pyrrolidino, piperidino, homopiperidino, 2-oxopyrrolidinyl,2-oxopiperidinyl, morpholino, piperazino, tetrahydropyranyl,thiomorpholino, dihydroindolyl, and the like. When the heterocycloalkylring is unsaturated it can contain one or two ring double bonds providedthat the ring is not aromatic. When the heterocycloalkyl group containsat least one nitrogen atom, it may also be referred to herein asheterocycloamino and is a subset of the heterocycloalkyl group. When theheterocycloalkyl group is a saturated ring and is not fused to aryl orheteroaryl ring as stated above, it may be referred to herein as asaturated monocyclic heterocycloalkyl. Examples of cycloalkyl include,but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.Examples of heterocycloalkyl include, but are not limited to,1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like. A “cycloalkylene” and a“heterocycloalkylene,” alone or as part of another substituent means adivalent radical derived from a cycloalkyl and heterocycloalkyl,respectively.

“Heterocycloamino” as used herein means a saturated or unsaturatedmonovalent monocyclic group (e.g., having 4 to 8 ring atoms) in whichone or more (e.g., 2) ring atoms is a heteroatom selected from N, O, orS(O)_(n″), where n″ is an integer from 0 to 2, the remaining ring atomsbeing carbon provided that at least one of the ring atoms is nitrogen.Additionally, one or more (e.g., 2) ring carbon atoms in theheterocycloamino ring can optionally be replaced by a —CO— group. Whenthe heterocycloamino ring is unsaturated it can contain one or more(e.g., two) ring double bonds provided that the ring is not aromatic.Unless otherwise stated, the heterocyloamino ring can optionally besubstituted with one, two, or three substituents (e.g., independentlyselected from saturated unsubstituted alkyl, hydroxyl, saturatedunsubstituted alkoxy, amino, saturated unsubstituted alkylamino, orsaturated unsubstituted dialkylamino). Heterocycloamino is a subset ofheterocycle defined above.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl,” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“halo(C₁-C₄)alkyl” is meant to include, but not be limited to,fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl,4-chlorobutyl, 3-bromopropyl, and the like.

The term “acyl” means —C(O)R where R is a substituted or unsubstitutedalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl.

The term “aryl” means, unless otherwise stated, an aromatic substituentwhich can be a single ring or multiple rings (preferably from 1 to 3rings) which may be fused together (i.e. a fused ring aryl) or linkedcovalently. A fused ring aryl refers to multiple rings fused togetherwherein at least one of the fused rings is an aryl ring (e.g., phenyl,1-naphthyl, 2-naphthyl, or 4-biphenyl). The term “heteroaryl” refers toaryl groups (or rings) that contain one or more (e.g., 4) heteroatomsselected from N, O, and S, wherein the nitrogen and sulfur atoms areoptionally oxidized, and the nitrogen atom(s) are optionallyquaternized, the remaining ring atoms being carbon. The heteroaryl maybe a monovalent monocyclic, bicyclic, or tricyclic (e.g., monocyclic orbicyclic) aromatic radical of 5 to 14 (e.g., 5 to 10) ring atoms whereone or more, (e.g., one, two, or three or four) ring atoms areheteroatom selected from N, O, or S. Examples include, but are notlimited to, thienyl, isoindolyl, benzoxazolyl, pyridazinyl, triazolyl,tetrazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl,2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl,5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl,4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl,5-benzothiazolyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl,5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and6-quinolyl. Thus, the term “heteroaryl” includes fused ring heteroarylgroups (i.e. multiple rings fused together wherein at least one of thefused rings is a heteroaromatic ring). A 5,6-fused ring heteroarylrefers to two rings fused together, wherein one ring has 5 members andthe other ring has 6 members, and wherein at least one ring is aheteroaryl ring. Likewise, a 6,6-fused ring heteroaryl refers to tworings fused together, wherein one ring has 6 members and the other ringhas 6 members, and wherein at least one ring is a heteroaryl ring. And a6,5-fused ring heteroaryl refers to two rings fused together, whereinone ring has 6 members and the other ring has 5 members, and wherein atleast one ring is a heteroaryl ring. A heteroaryl group can be attachedto the remainder of the molecule through a carbon or heteroatom. An“arylene” and a “heteroarylene,” alone or as part of another substituentmeans a divalent radical derived from an aryl and heteroaryl,respectively.

The terms “arylalkyl” and “heteroarylalkyl” is meant to include thoseradicals in which an aryl group or a heteroaryl group is attached to analkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like)including those alkyl groups in which a carbon atom (e.g., a methylenegroup) has been replaced by, for example, an oxygen atom (e.g.,phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and thelike).

The term “oxo” as used herein means an oxygen that is double bonded to acarbon atom. The term “carbonyl” as used herein refers to a —C(O)—group.

The symbol “

” indicates, as customary in the art, the point of attachment of asubstituent.

“Optional” or “optionally” means that the subsequently described eventor circumstance may but need not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not. For example, “heterocycloalkyl group optionallysubstituted with an alkyl group” means that the alkyl may but need notbe present, and the description includes situations where theheterocycloalkyl group is substituted with an alkyl group and situationswhere the heterocycloalkyl group is not substituted with alkyl.

The term “alkylsulfonyl” as used herein means a moiety having theformula —S(O₂)—R′, where R′ is an alkyl group as defined above. R′ mayhave a specified number of carbons (e.g., “C₁-C₄ alkylsulfonyl”).

Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl” and“heteroaryl”) are meant to include both substituted and unsubstitutedforms of the indicated radical unless stated otherwise.

Substituents for the alkyl and heteroalkyl radicals (including thosegroups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) can be one or more of a variety of groups selectedfrom, but not limited to: —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′,-halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR′—C(NR′R″R′″)═NR″″,—NR—C(NR′R″)═NR″″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —CN and—NO₂ in a number ranging from zero to (2m′+1), where m′ is the totalnumber of carbon atoms in such radical. R′, R″, R′″ and R″″ eachindependently refer to hydrogen, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g.,aryl substituted with 1-3 halogens), substituted or unsubstituted alkyl,alkoxy or thioalkoxy groups, or arylalkyl groups. When a compound of theinvention includes more than one R group, for example, each of the Rgroups is independently selected as are each R′, R″, R′″ and R″″ groupswhen more than one of these groups is present. When R′ and R″ areattached to the same nitrogen atom, they can be combined with thenitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example,—NR′R″ is meant to include, but not be limited to, 1-pyrrolidinyl and4-morpholinyl. From the above discussion of substituents, one of skillin the art will understand that the term “alkyl” is meant to includegroups including carbon atoms bound to groups other than hydrogengroups, such as haloalkyl (e.g., —CF₃ and —CH₂CF₃) and acyl (e.g.,—C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and the like).

Similar to the substituents described for the alkyl radical,substituents for the aryl and heteroaryl groups are varied and may beselected from, for example: halogen, —OR′, —NR′R″, —SR′, -halogen,—SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR′R″, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″″,—NR′—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NR′SO₂R′, —CN and—NO₂, —R′, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy, and fluoro(C₁-C₄)alkyl,in a number ranging from zero to the total number of open valences onthe aromatic ring system; and where R′, R″, R′″ and R″″ are preferablyindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl and substituted or unsubstitutedheteroaryl. When a compound of the invention includes more than one Rgroup, for example, each of the R groups is independently selected asare each R′, R″, R′″ and R″″ groups when more than one of these groupsis present.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally form a ring of the formula -T-C(O)—(CRR′)_(q)—U—, whereinT and U are independently —NR—, —O—, —CRR′— or a single bond, and q isan integer of from 0 to 3. Alternatively, two of the substituents onadjacent atoms of the aryl or heteroaryl ring may optionally be replacedwith a substituent of the formula -A-(CH₂)_(r)—B—, wherein A and B areindependently —CRR′—, —O—, —NR—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or asingle bond, and r is an integer of from 1 to 4. One of the single bondsof the new ring so formed may optionally be replaced with a double bond.Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula —(CRR′)_(s)—X′—(C″R′″)_(d)—, where s and d are independentlyintegers of from 0 to 3, and X′ is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or—S(O)₂NR′—. The substituents R, R′, R″ and R′″ are preferablyindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl.

Unless otherwise stated, the term “heteroatom” or “ring heteroatom” ismeant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P),and silicon (Si).

A “substituent group,” as used herein, means a group selected from thefollowing moieties:

(A) —OH, —NH₂, —SH, —CN, —CF₃, —NO₂, oxo, halogen, unsubstituted alkyl,unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstitutedheterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and

(B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl, substituted with at least one substituent selected from:

(i) oxo, —OH, —NH₂, —SH, —CN, —CF₃, —NO₂, halogen, unsubstituted alkyl,unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstitutedheterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and

(ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl, substituted with at least one substituent selected from:

(a) oxo, —OH, —NH₂, —SH, —CN, —CF₃, —NO₂, halogen, unsubstituted alkyl,unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstitutedheterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and

(b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, orheteroaryl, substituted with at least one substituent selected from oxo,—OH, —NH₂, —SH, —CN, —CF₃, —NO₂, halogen, unsubstituted alkyl,unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstitutedheterocycloalkyl, unsubstituted aryl, and unsubstituted heteroaryl.

A “size-limited substituent” or “size-limited substituent group,” asused herein means a group selected from all of the substituentsdescribed above for a “substituent group,” wherein each substituted orunsubstituted alkyl is a substituted or unsubstituted C₁-C₂₀ alkyl, eachsubstituted or unsubstituted heteroalkyl is a substituted orunsubstituted 2 to 20 membered heteroalkyl, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted C₄-C₈cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is asubstituted or unsubstituted 4 to 8 membered heterocycloalkyl.

A “lower substituent” or “lower substituent group,” as used herein meansa group selected from all of the substituents described above for a“substituent group,” wherein each substituted or unsubstituted alkyl isa substituted or unsubstituted C₁-C₈ alkyl, each substituted orunsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8membered heteroalkyl, each substituted or unsubstituted cycloalkyl is asubstituted or unsubstituted C₅-C₇ cycloalkyl, and each substituted orunsubstituted heterocycloalkyl is a substituted or unsubstituted 5 to 7membered heterocycloalkyl.

Unless indicated otherwise, the term “derivative” in the context of acompound disclosed herein refers to a compound afforded by chemicalmodification, e.g., by the bonding of one or more substituent groups asdescribed herein.

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds which are prepared with relatively nontoxicacids or bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present inventioncontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable base additionsalts include sodium, potassium, calcium, ammonium, organic amino, ormagnesium salt, or a similar salt. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic,suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and thelike. Also included are salts of amino acids such as arginate and thelike, and salts of organic acids like glucuronic or galactunoric acidsand the like. See e.g., Berge et al., “Pharmaceutical Salts”, Journal ofPharmaceutical Science, 1977, 66, 1-19). Additional information onsuitable pharmaceutically acceptable salts can be found in REMINGTON'SPHARMACEUTICAL SCIENCES, 17th ed., Mack Publishing Company, Easton, Pa.,1985, which is incorporated herein by reference. Certain specificcompounds of the present invention contain both basic and acidicfunctionalities that allow the compounds to be converted into eitherbase or acid addition salts.

Thus, the compounds disclosed herein may exist as salts. Examples ofsuch salts include hydrochlorides, hydrobromides, sulfates,methanesulfonates, nitrates, maleates, acetates, citrates, fumarates,tartrates (e.g., (+)-tartrates, (−)-tartrates or mixtures thereofincluding racemic mixtures), succinates, benzoates and salts with aminoacids such as glutamic acid. These salts may be prepared by methodsknown to those skilled in the art.

The neutral forms of the compounds are preferably regenerated bycontacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compounddiffers from the various salt forms in certain physical properties, suchas solubility in polar solvents.

The term “prodrug” is used according to its plain ordinary meaning andis intended to mean compounds that require a chemical or enzymatictransformation in order to release the active parent drug in vivo priorto producing a pharmacological effect.

The compounds of the present invention may have asymmetric centersand/or geometric isomers. Compounds of the present invention containingan asymmetrically substituted atom may be isolated in optically activeor racemic forms. It is well known in the art how to prepare opticallyactive forms, such as by resolution of materials. All chiral,diastereomeric, racemic forms are within the scope of this invention,unless the specific stereochemistry or isomeric form is specificallyindicated. All possible tautomers and cis and trans isomers, asindividual forms and mixtures thereof are within the scope of thisinvention. Additionally, as used herein the term alkyl includes all thepossible isomeric forms of the alkyl group albeit only a few examplesare set forth. Furthermore, when the cyclic groups such as aryl,heteroaryl, heterocycloalkyl are substituted, they include all thepositional isomers albeit only a few examples are set forth.Furthermore, all polymorphic forms, including amorphous form, andhydrates of a compound disclosed herein are within the scope of thisinvention.

Certain compounds of the present invention possess asymmetric carbonatoms (optical centers) or double bonds; the racemates, diastereomers,tautomers, geometric isomers and individual isomers are encompassedwithin the scope of the present invention, as are enantiomers. Thecompounds of the present invention do not include those which are knownin the art to be too unstable to synthesize and/or isolate.

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present invention, whether radioactive or not, areencompassed within the scope of the present invention.

Where a substituent of a compound provided herein is “R-substituted”(e.g., R⁷-substituted), it is meant that the substituent is substitutedwith one or more of the named R groups (e.g., R⁷) as appropriate. Eachappearance of the substituent may be different. In some embodiments, thesubstituent is substituted with only one of the named R groups. Each ofthe numbered R substituents provided herein may be alternativelyreferred to as a primed number such as a first prime (′), a second prime(″), a third prime (′″) and so on. For example, R⁷ may be alternativelyreferred to as R^(7′), R^(7″), R^(7′″) and so on. Unless otherwisenoted, the primed number of the R substituent is accorded the samedefinition as the R substituent itself, but where the primed number ofthe R substituent is optionally different from the R substituent itselfwhen both appear in a compound disclosed herein. For example, R⁷ andR^(7′), unless otherwise stated, are independently chosen from the sameMarkush group definition.

A “pharmaceutically acceptable carrier” or “pharmaceutically acceptableexcipient” means a carrier or an excipient that is useful in preparing apharmaceutical composition that is generally safe, non-toxic and neitherbiologically nor otherwise undesirable, and includes a carrier or anexcipient that is acceptable for veterinary use as well as humanpharmaceutical use. “A pharmaceutically acceptable carrier/excipient” asused in the specification and claims includes both one and more than onesuch excipient.

The terms “treating” or “treatment” refers to any indicia of success inthe treatment or amelioration of an injury, pathology or condition,including any objective or subjective parameter such as abatement;remission; diminishing of symptoms or making the injury, pathology orcondition more tolerable to the patient; slowing in the rate ofdegeneration or decline; making the final point of degeneration lessdebilitating; improving a patient's physical or mental well-being. Thetreatment or amelioration of symptoms can be based on objective orsubjective parameters; including the results of a physical examination,neuropsychiatric exams, and/or a psychiatric evaluation. For example,the certain methods presented herein successfully treat cancer bydecreasing the incidence of cancer, in inhibiting its growth and orcausing remission of cancer.

An “effective amount” of a compound is an amount sufficient tocontribute to the treatment, prevention, or reduction of a symptom orsymptoms of a disease. Where recited in reference to a diseasetreatment, an “effective amount” may also be referred to as a“therapeutically effective amount.” A “reduction” of a symptom orsymptoms (and grammatical equivalents of this phrase) means decreasingof the severity or frequency of the symptom(s), or elimination of thesymptom(s). A “prophylactically effective amount” of a drug is an amountof a drug that, when administered to a subject, will have the intendedprophylactic effect, e.g., preventing or delaying the onset (orreoccurrence) a disease, disorder or condition, or reducing thelikelihood of the onset (or reoccurrence) of a disease, disorder orcondition or symptoms thereof. The full prophylactic effect does notnecessarily occur by administration of one dose, and may occur onlyafter administration of a series of doses. Thus, a prophylacticallyeffective amount may be administered in one or more administrations.

The term “topical” in the context of methods described herein relates inthe customary sense to the administration of a compound orpharmaceutical composition which is incorporated into a suitablepharmaceutical carrier and administered at a topical treatment site of asubject. Accordingly, the term “topical pharmaceutical composition”includes those pharmaceutical forms in which the compound isadministered externally by direct contact with a topical treatment site,e.g., the eye or the skin. The term “topical ocular pharmaceuticalcomposition” refers to a pharmaceutical composition suitable foradministering directly to the eye. The term “topical epidermalpharmaceutical composition” refers to a pharmaceutical compositionsuitable for administering directed to the epidermal layer of the skin,e.g., the palpebra, the supercilium, the scalp, or the body. The term“topical administering” refers to administering externally by directcontact with a topical treatment site. The term “topical epidermaladministering” refers to administering externally by direct contact withthe epidermis. The term “topical ocular administering” refers toadministering externally by direct contact with the eye.

Methods of administering to the skin may include “topical palpebraadministering” which refers to administering to the palpebra (i.e.,eyelid) and especially the portion of the palpebra from which the cilia(i.e., eyelashes) grow. Methods of administering to the skin furtherinclude “topical supercilium administering” which refers toadministering to the supercilium (i.e., the ridge above the eye) fromwhich the supercilia (i.e., eyebrows) grow. Methods of administering tothe skin further include “topical scalp administering” which refers toadministering directly to the scalp. Methods of administering to theskin further include “topical body administering” which refers toadministering directly to parts of the body excluding the scalp.

Conventional pharmaceutical forms for this purpose include ointments,liniments, creams, shampoos, lotions, pastes, jellies, sprays, aerosols,and the like, and may be applied in patches or impregnated dressingsdepending on the part of the body to be treated. The term “ointment”embraces formulations (including creams) having oleaginous,water-soluble and emulsion-type bases, e.g., petrolatum, lanolin,polyethylene glycols, as well as mixtures of these.

The term “piliation” refers in the customary sense to the formation andgrowth of hair. Accordingly, piliation and “hair growth” are usedsynonymously herein.

II. Compounds

In a first aspect, there is provided a compound with structure ofFormula (I),

or derivative, isomer, or enantiomer thereof. Referring to Formula (I),R¹ is hydrogen or R^(1a)C(O)—. R² is hydrogen or R^(2a)C(O)—. R³ ishydrogen or R^(3a)C(O)—. R^(1a), R^(2a) and R^(3a) are independentlysubstituted or unsubstituted C₁-C₁₀ alkyl (e.g., substituted orunsubstituted C₁-C₁₀ saturated alkyl), substituted or unsubstitutedC₃-C₈ cycloalkyl, or substituted or unsubstituted aryl. In oneembodiment, R^(1a), R^(2a) and R^(3a) are independently hydrogen,substituted or unsubstituted C₁-C₁₀ alkyl (e.g., substituted orunsubstituted C₁-C₁₀ saturated alkyl), substituted or unsubstitutedC₃-C₈ cycloalkyl, or substituted or unsubstituted aryl. R⁴ and R⁵ areindependently hydrogen, substituted or unsubstituted C₁-C₁₀ alkyl (e.g.,substituted or unsubstituted C₁-C₁₀ saturated alkyl), or substituted orunsubstituted C₃-C₈ cycloalkyl. In some embodiments, at least one of R¹,R² and R³ is not hydrogen.

In one embodiment, R^(1a), R^(2a) and R^(3a) are independentlysubstituted or unsubstituted C₁-C₆ alkyl (e.g., substituted orunsubstituted C₁-C₆ saturated alkyl). In one embodiment, R^(1a), R^(2a)and R^(3a) are independently substituted or unsubstituted C₁-C₃ alkyl(e.g., substituted or unsubstituted C₁-C₃ saturated alkyl). In oneembodiment, R^(1a), R^(2a) and R^(3a) are independently substituted orunsubstituted C₁ alkyl. In one embodiment, R^(1a), R^(2a) and R^(3a) areindependently methyl.

In one embodiment, R^(1a), R^(2a) and R^(3a) are independentlyunsubstituted C₁-C₆ alkyl (e.g., unsubstituted C₁-C₆ saturated alkyl).In one embodiment, R^(1a), R^(2a) and R^(3a) are independentlyunsubstituted C₁-C₃ alkyl (e.g., unsubstituted C₁-C₃ saturated alkyl).In one embodiment, R^(1a), R^(2a) and R^(3a) are independentlyunsubstituted C₁ alkyl.

In one embodiment, R^(1a), R^(2a) and R^(3a) are independentlysubstituted or unsubstituted C₃-C₈ cycloalkyl (e.g., substituted orunsubstituted C₃-C₆ cycloalkyl).

In one embodiment, R^(1a), R^(2a) and R^(3a) are independentlysubstituted or unsubstituted aryl. In one embodiment, R^(1a), R^(2a) andR^(3a) are independently unsubstituted aryl. In one embodiment, R^(1a),R^(2a) and R^(3a) are independently substituted or unsubstituted phenyl.In one embodiment, R^(1a), R^(2a) and R^(3a) are independentlyunsubstituted phenyl.

In some embodiments with structure of Formula (I), at least one of R¹,R² and R³ is not hydrogen. For example, in some embodiments, R¹ is nothydrogen, R² is not hydrogen, or R³ is not hydrogen. In someembodiments, each of R¹ and R², each of R¹ and R³, each of R² and R³, oreach of R¹ and R² and R³ is not hydrogen. In one embodiment, two of R¹,R² and R³ are not hydrogen. In one embodiment, all of R¹, R² and R³ arenot hydrogen.

In one embodiment, the compound with structure of Formula (I) has thestructure of one of Formulae (II), (III) or (IV), or derivative, isomer,or enantiomer thereof:

In some embodiments of Formula (II), R¹ is R^(1a)C(O)— and R⁴ and R⁵ areas defined herein (including embodiments thereof). In some embodimentsof Formula (III), R² is R^(2a)C(O)— and R⁴ and R⁵ are as defined herein(including embodiments thereof). In some embodiments of Formula (IV), R³is R^(3a)C(O)—, and R⁴ and R⁵ are as defined herein (includingembodiments thereof).

In one embodiment of Formulae (I), (II), (III) or (IV), R^(1a) isR^(6a)-substituted or unsubstituted C₁-C₁₀ alkyl (e.g.,R^(6a)-substituted or unsubstituted C₁-C₁₀ saturated alkyl),R^(6a)-substituted or unsubstituted C₃-C₈ cycloalkyl, orR^(6a)-substituted or unsubstituted aryl. R^(6a) is halogen, —CN, —CF₃,—OH, —NO₂, —C(O)NH₂, —SH, —NH₂, —SO₂, —COOH, R^(6b)-substituted orunsubstituted alkyl (e.g., R^(6b)-substituted or unsubstituted saturatedalkyl), R^(6b)-substituted or unsubstituted heteroalkyl,R^(6b)-substituted or unsubstituted cycloalkyl, R^(6b)-substituted orunsubstituted heterocycloalkyl, R^(6b)-substituted or unsubstitutedaryl, or R^(6b)-substituted or unsubstituted heteroaryl. R^(6b) ishalogen, —CN, —CF₃, —OH, —NO₂, —C(O)NH₂, —SH, —NH₂, —SO₂, —COOH,R^(6c)-substituted or unsubstituted alkyl (e.g., R^(6c)-substituted orunsubstituted saturated alkyl), R^(6c)-substituted or unsubstitutedheteroalkyl, R^(6c)-substituted or unsubstituted cycloalkyl,R^(6c)-substituted or unsubstituted heterocycloalkyl, R^(6c)-substitutedor unsubstituted aryl, or R^(6c)-substituted or unsubstitutedheteroaryl. R^(6c) is halogen, —CN, —CF₃, —OH, —NO₂, —C(O)NH₂, —SH,—NH₂, —SO₂, —COOH, unsubstituted alkyl (e.g., unsubstituted saturatedalkyl), unsubstituted heteroalkyl, unsubstituted cycloalkyl,unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstitutedheteroaryl.

In some embodiments of Formulae (I), (II), (III) or (IV), R^(1a) isunsubstituted C₁-C₁₀ alkyl (e.g., unsubstituted C₁-C₁₀ saturated alkyl),unsubstituted C₃-C₈ cycloalkyl, or unsubstituted aryl (e.g., phenyl). Insome embodiments, R^(1a) is unsubstituted C₁-C₁₀ alkyl (e.g.,unsubstituted C₁-C₁₀ saturated alkyl), or unsubstituted aryl (e.g.,phenyl). In some embodiments, R^(1a) is unsubstituted C₁-C₅ alkyl (e.g.,unsubstituted C₁-C₅ saturated alkyl), or unsubstituted aryl (e.g.,phenyl).

In some embodiments of Formulae (I), (II), (III) or (IV), R^(6a) ishalogen, —CN, —CF₃, —OH, —NO₂, —C(O)NH₂, —SH, —NH₂, —SO₂, —COOH,R^(6b)-substituted or unsubstituted C₁-C₁₀ alkyl (e.g.,R^(6b)-substituted or unsubstituted C₁-C₁₀ saturated alkyl),R^(6b)-substituted or unsubstituted 2 to 10 membered heteroalkyl,R^(6b)-substituted or unsubstituted C₃-C₈ cycloalkyl, R^(6b)-substitutedor unsubstituted 3 to 8 membered heterocycloalkyl, R^(6b)-substituted orunsubstituted aryl, or R^(6b)-substituted or unsubstituted 5-6 memberedheteroaryl. In some embodiments, R^(6b) is halogen, —CN, —CF₃, —OH,—NO₂, —C(O)NH₂, —SH, —NH₂, —SO₂, —COOH, R^(6c)-substituted orunsubstituted C₁-C₁₀ alkyl (e.g., R^(6c)-substituted or unsubstitutedsaturated C₁-C₁₀ alkyl), R^(6c)-substituted or unsubstituted 2 to 10membered heteroalkyl, R^(6c)-substituted or unsubstituted C₃-C₈cycloalkyl, R^(6c)-substituted or unsubstituted 3 to 8 memberedheterocycloalkyl, R^(6c)-substituted or unsubstituted aryl, orR^(6c)-substituted or unsubstituted 5-6 membered heteroaryl. In someembodiments, R^(6c) is halogen, —CN, —CF₃, —OH, —NO₂, —C(O)NH₂, —SH,—NH₂, —SO₂, —COOH, unsubstituted C₁-C₁₀ alkyl (e.g., unsubstitutedC₁-C₁₀ saturated alkyl), unsubstituted 2 to 10 membered heteroalkyl,unsubstituted C₃-C₈ cycloalkyl, unsubstituted 3 to 8 memberedheterocycloalkyl, unsubstituted aryl, or unsubstituted 5-6 memberedheteroaryl.

In some embodiments of Formulae (I), (II), (III) or (IV), R^(6a) isR^(6b)-substituted or unsubstituted C₁-C₁₀ alkyl (e.g.,R^(6b)-substituted or unsubstituted saturated C₁-C₁₀ alkyl),R^(6b)-substituted or unsubstituted C₃-C₈ cycloalkyl, orR^(6b)-substituted or unsubstituted aryl. In some embodiments, R^(6b) isR^(6c)-substituted or unsubstituted C₁-C₁₀ alkyl (e.g.,R^(6c)-substituted or unsubstituted saturated C₁-C₁₀ alkyl),R^(6c)-substituted or unsubstituted C₃-C₈ cycloalkyl orR^(6c)-substituted or unsubstituted aryl. In some embodiments, R^(6c) isunsubstituted C₁-C₁₀ alkyl (e.g., unsubstituted C₁-C₁₀ saturated alkyl),unsubstituted C₃-C₈ cycloalkyl, or unsubstituted aryl.

In some embodiments of Formulae (I), (II), (III) or (IV), R^(6a) isunsubstituted C₁-C₁₀ alkyl (e.g., unsubstituted C₁-C₁₀ saturated alkyl),unsubstituted C₃-C₈ cycloalkyl, or unsubstituted aryl. In someembodiments, R^(6a) is unsubstituted C₁-C₁₀ alkyl (e.g., unsubstitutedC₁ to C₁₀ saturated alkyl). In some embodiments, R^(6a) is unsubstitutedC₁-C₄ alkyl (e.g., unsubstituted C₁ to C₄ saturated alkyl). In someembodiments, R^(6a) is unsubstituted C₃-C₈ cycloalkyl. In someembodiments, R^(6a) is unsubstituted aryl (e.g., phenyl).

In one embodiment of Formulae (I), (II), (III) or (IV), R^(2a) isR^(7a)-substituted or unsubstituted C₁-C₁₀ alkyl (e.g.,R^(7a)-substituted or unsubstituted C₁-C₁₀ saturated alkyl),R^(7a)-substituted or unsubstituted C₃-C₈ cycloalkyl, orR^(7a)-substituted or unsubstituted aryl. R^(7a) is halogen, —CN, —CF₃,—OH, —NO₂, —C(O)NH₂, —SH, —NH₂, —SO₂, —COOH, R^(7b)-substituted orunsubstituted alkyl (R^(7b)-substituted or unsubstituted saturatedalkyl), R^(7b)-substituted or unsubstituted heteroalkyl,R^(7b)-substituted or unsubstituted cycloalkyl, R^(7b)-substituted orunsubstituted heterocycloalkyl, R^(7b)-substituted or unsubstitutedaryl, or R^(7b)-substituted or unsubstituted heteroaryl. R^(7b) ishalogen, —CN, —CF₃, —OH, —NO₂, —C(O)NH₂, —SH, —NH₂, —SO₂, —COOH,R^(7c)-substituted or unsubstituted alkyl (e.g., R^(7c)-substituted orunsubstituted saturated alkyl), R^(7c)-substituted or unsubstitutedheteroalkyl, R^(7c)-substituted or unsubstituted cycloalkyl,R^(7c)-substituted or unsubstituted heterocycloalkyl, R^(7c)-substitutedor unsubstituted aryl, or R^(7c)-substituted or unsubstitutedheteroaryl. R^(7c) is halogen, —CN, —CF₃, —OH, —NO₂, —C(O)NH₂, —SH,—NH₂, —SO₂, —COOH, unsubstituted alkyl (e.g., unsubstituted saturatedalkyl), unsubstituted heteroalkyl, unsubstituted cycloalkyl,unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstitutedheteroaryl.

In some embodiments of Formulae (I), (II), (III) or (IV), R^(2a) isunsubstituted C₁-C₁₀ alkyl (e.g., unsubstituted C₁-C₁₀ saturated alkyl),unsubstituted C₃-C₈ cycloalkyl, or unsubstituted aryl (e.g., phenyl). Insome embodiments, R^(2a) is unsubstituted C₁-C₁₀ alkyl (e.g.,unsubstituted C₁-C₁₀ saturated alkyl), or unsubstituted aryl (e.g.,phenyl). In some embodiments, R^(2a) is unsubstituted C₁-C₅ alkyl (e.g.,unsubstituted C₁-C₅ saturated alkyl), or unsubstituted aryl (e.g.,phenyl).

In some embodiments of Formulae (I), (II), (III) or (IV), R^(7a) ishalogen, —CN, —CF₃, —OH, —NO₂, —C(O)NH₂, —SH, —NH₂, —SO₂, —COOH,R^(7b)-substituted or unsubstituted C₁-C₁₀ alkyl (e.g.,R^(7b)-substituted or unsubstituted saturated C₁-C₁₀ alkyl),R^(7b)-substituted or unsubstituted 2 to 10 membered heteroalkyl,R^(7b)-substituted or unsubstituted C₃-C₈ cycloalkyl, R^(7b)-substitutedor unsubstituted 3 to 8 membered heterocycloalkyl, R^(7b)-substituted orunsubstituted aryl, or R^(7b)-substituted or unsubstituted 5-6 memberedheteroaryl. In some embodiments, R^(7b) is halogen, —CN, —CF₃, —OH,—NO₂, —C(O)NH₂, —SH, —NH₂, —SO₂, —COOH, R^(7c)-substituted orunsubstituted C₁-C₁₀ alkyl (e.g., R^(7c)-substituted or unsubstitutedsaturated C₁-C₁₀ alkyl), R^(7c)-substituted or unsubstituted 2 to 10membered heteroalkyl, R^(7c)-substituted or unsubstituted C₃-C₈cycloalkyl, R^(7c)-substituted or unsubstituted 3 to 8 memberedheterocycloalkyl, R^(7c)-substituted or unsubstituted aryl, orR^(7c)-substituted or unsubstituted 5-6 membered heteroaryl. In someembodiments, R^(7c) is halogen, —CN, —CF₃, —OH, —NO₂, —C(O)NH₂, —SH,—NH₂, —SO₂, —COOH, unsubstituted C₁-C₁₀ alkyl (e.g., unsubstitutedC₁-C₁₀ saturated alkyl), unsubstituted 2 to 10 membered heteroalkyl,unsubstituted C₃-C₈ cycloalkyl, unsubstituted 3 to 8 memberedheterocycloalkyl, unsubstituted aryl, or unsubstituted 5-6 memberedheteroaryl.

In some embodiments of Formulae (I), (II), (III) or (IV), R^(7a) isR^(7b)-substituted or unsubstituted C₁-C₁₀ alkyl (e.g.,R^(7b)-substituted or unsubstituted saturated C₁-C₁₀ alkyl),R^(7b)-substituted or unsubstituted C₃-C₈ cycloalkyl, orR^(7b)-substituted or unsubstituted aryl. In some embodiments, R^(7b) isR^(7c)-substituted or unsubstituted C₁-C₁₀ alkyl (e.g.,R^(7c)-substituted or unsubstituted saturated C₁-C₁₀ alkyl),R^(7c)-substituted or unsubstituted C₃-C₈ cycloalkyl orR^(7c)-substituted or unsubstituted aryl. In some embodiments, R^(7c) isunsubstituted C₁-C₁₀ alkyl (e.g., unsubstituted C₁-C₁₀ saturated alkyl),unsubstituted C₃-C₈ cycloalkyl, or unsubstituted aryl.

In some embodiments of Formulae (I), (II), (III) or (IV), R^(7a) isunsubstituted C₁-C₁₀ alkyl (e.g., unsubstituted C₁-C₁₀ saturated alkyl),unsubstituted C₃-C₈ cycloalkyl, or unsubstituted aryl. In someembodiments, R^(7a) is unsubstituted C₁-C₁₀ alkyl (e.g., unsubstitutedC₁ to C₁₀ saturated alkyl). In some embodiments, R^(7a) is unsubstitutedC₁-C₄ alkyl (e.g., unsubstituted C₁ to C₄ saturated alkyl). In someembodiments, R^(7a) is unsubstituted C₃-C₈ cycloalkyl. In someembodiments, R^(7a) is unsubstituted aryl (e.g., phenyl).

In one embodiment of Formulae (I), (II), (III) or (IV), R^(3a) isR^(8a)-substituted or unsubstituted C₁-C₁₀ alkyl (e.g.,R^(8a)-substituted or unsubstituted C₁-C₁₀ saturated alkyl),R^(8a)-substituted or unsubstituted C₃-C₈ cycloalkyl, orR^(8a)-substituted or unsubstituted aryl. R^(8a) is halogen, —CN, —CF₃,—OH, —NO₂, —C(O)NH₂, —SH, —NH₂, —SO₂, —COOH, R^(8b)-substituted orunsubstituted alkyl (R^(8b)-substituted or unsubstituted saturatedalkyl), R^(8b)-substituted or unsubstituted heteroalkyl,R^(8b)-substituted or unsubstituted cycloalkyl, R^(8b)-substituted orunsubstituted heterocycloalkyl, R^(8b)-substituted or unsubstitutedaryl, or R^(8b)-substituted or unsubstituted heteroaryl. R^(8b) ishalogen, —CN, —CF₃, —OH, —NO₂, —C(O)NH₂, —SH, —NH₂, —SO₂, —COOH,R^(8c)-substituted or unsubstituted alkyl (e.g., R^(8c)-substituted orunsubstituted saturated alkyl), R^(8c)-substituted or unsubstitutedheteroalkyl, R^(8c)-substituted or unsubstituted cycloalkyl,R^(8c)-substituted or unsubstituted heterocycloalkyl, R^(8c)-substitutedor unsubstituted aryl, or R^(8c)-substituted or unsubstitutedheteroaryl. R^(8c) is halogen, —CN, —CF₃, —OH, —NO₂, C(O)NH₂, —SH, —NH₂,—SO₂, —COOH, unsubstituted alkyl (e.g., unsubstituted saturated alkyl),unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstitutedheterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

In some embodiments of Formulae (I), (II), (III) or (IV), R^(3a) isunsubstituted C₁-C₁₀ alkyl (e.g., unsubstituted C₁-C₁₀ saturated alkyl),unsubstituted C₃-C₈ cycloalkyl, or unsubstituted aryl (e.g., phenyl). Insome embodiments, R^(3a) is unsubstituted C₁-C₁₀ alkyl (e.g.,unsubstituted C₁-C₁₀ saturated alkyl), or unsubstituted aryl (e.g.,phenyl). In some embodiments, R^(3a) is unsubstituted C₁-C₅ alkyl (e.g.,unsubstituted C₁-C₅ saturated alkyl), or unsubstituted aryl (e.g.,phenyl).

In some embodiments of Formulae (I), (II), (III) or (IV), R^(8a) ishalogen, —CN, —CF₃, —OH, —NO₂, —C(O)NH₂, —SH, —NH₂, —SO₂, —COOH,R^(8b)-substituted or unsubstituted C₁-C₁₀ alkyl (e.g.,R^(8b)-substituted or unsubstituted saturated C₁-C₁₀ alkyl),R^(8b)-substituted or unsubstituted 2 to 10 membered heteroalkyl,R^(8b)-substituted or unsubstituted C₃-C₈ cycloalkyl, R^(8b)-substitutedor unsubstituted 3 to 8 membered heterocycloalkyl, R^(8b)-substituted orunsubstituted aryl, or R^(8b)-substituted or unsubstituted 5-6 memberedheteroaryl. In some embodiments, R^(8b) is halogen, —CN, —CF₃, —OH,—NO₂, —C(O)NH₂, —SH, —NH₂, —SO₂, —COOH, R^(8c)-substituted orunsubstituted C₁-C₁₀ alkyl (e.g., R^(8c)-substituted or unsubstitutedsaturated C₁-C₁₀ alkyl), R^(8c)-substituted or unsubstituted 2 to 10membered heteroalkyl, R^(8c)-substituted or unsubstituted C₃-C₈cycloalkyl, R^(8c)-substituted or unsubstituted 3 to 8 memberedheterocycloalkyl, R^(8c)-substituted or unsubstituted aryl, orR^(8c)-substituted or unsubstituted 5-6 membered heteroaryl. In someembodiments, R^(8c) is halogen, —CN, —CF₃, —OH, —NO₂, —C(O)NH₂, —SH,—NH₂, —SO₂, —COOH, unsubstituted C₁-C₁₀ alkyl (e.g., unsubstitutedC₁-C₁₀ saturated alkyl), unsubstituted 2 to 10 membered heteroalkyl,unsubstituted C₃-C₈ cycloalkyl, unsubstituted 3 to 8 memberedheterocycloalkyl, unsubstituted aryl, or unsubstituted 5-6 memberedheteroaryl.

In some embodiments of Formulae (I), (II), (III) or (IV), R^(8a) isR^(8b)-substituted or unsubstituted C₁-C₁₀ alkyl (e.g.,R^(8b)-substituted or unsubstituted C₁-C₁₀ saturated alkyl),R^(8b)-substituted or unsubstituted C₃-C₈ cycloalkyl, orR^(8b)-substituted or unsubstituted aryl. In some embodiments, R^(8b) isR^(8c)-substituted or unsubstituted C₁-C₁₀ alkyl (e.g.,R^(8c)-substituted or unsubstituted C₁-C₁₀ saturated alkyl),R^(8c)-substituted or unsubstituted C₃-C₈ cycloalkyl orR^(8c)-substituted or unsubstituted aryl. In some embodiments, R^(8c) isunsubstituted C₁-C₁₀ alkyl (e.g., unsubstituted C₁-C₁₀ saturated alkyl),unsubstituted C₃-C₈ cycloalkyl, or unsubstituted aryl.

In some embodiments of Formulae (I), (II), (III) or (IV), R^(8a) isunsubstituted C₁-C₁₀ alkyl (e.g., unsubstituted C₁-C₁₀ saturated alkyl),unsubstituted C₃-C₈ cycloalkyl, or unsubstituted aryl. In someembodiments, R^(8a) is unsubstituted C₁-C₁₀ alkyl (e.g., unsubstitutedC₁ to C₁₀ saturated alkyl). In some embodiments, R^(8a) is unsubstitutedC₁-C₄ alkyl (e.g., unsubstituted C₁ to C₄ saturated alkyl). In someembodiments, R^(8a) is unsubstituted C₃-C₈ cycloalkyl. In someembodiments, R^(8a) is unsubstituted aryl (e.g., phenyl). In someembodiments, R^(1a), R^(2a) or R^(3a) are independently hydrogen or asubstituent provided herein.

In some embodiments of Formulae (I), (II), (III) or (IV), R⁴ ishydrogen. In other embodiments, R⁴ is substituted or unsubstitutedC₁-C₁₀ alkyl (e.g., substituted or unsubstituted C₁-C₁₀ saturatedalkyl), or substituted or unsubstituted C₃-C₈ cycloalkyl. In oneembodiment, R⁴ is substituted or unsubstituted C₁-C₆ alkyl (e.g.substituted or unsubstituted C₁-C₆ saturated alkyl). In one embodiment,R⁴ is substituted or unsubstituted C₁-C₃ alkyl (e.g. substituted orunsubstituted C₁-C₃ saturated alkyl). In one embodiment, R⁴ issubstituted or unsubstituted C₂ alkyl (e.g. substituted or unsubstitutedC₁-C₂ saturated alkyl). In one embodiment, R⁴ is ethyl. In oneembodiment, R⁴ is substituted or unsubstituted C₃-C₈ cycloalkyl.

In one embodiment of Formulae (I), (II), (III) or (IV), R⁴ isR^(9a)-substituted or unsubstituted C₁-C₁₀ alkyl (e.g.,R^(9a)-substituted or unsubstituted C₁-C₁₀ saturated alkyl), orR^(9a)-substituted or unsubstituted C₃-C₈ cycloalkyl. R^(9a) is halogen,—CN, —CF₃, —OH, —NO₂, —C(O)NH₂, —SH, —NH₂, —SO₂, —COOH,R^(9b)-substituted or unsubstituted alkyl (e.g., R^(9b)-substituted orunsubstituted saturated alkyl), R^(9b)-substituted or unsubstitutedheteroalkyl, R^(9b)-substituted or unsubstituted cycloalkyl,R^(9b)-substituted or unsubstituted heterocycloalkyl, R^(9b)-substitutedor unsubstituted aryl, or R^(9b)-substituted or unsubstitutedheteroaryl. R^(9b) is halogen, —CN, —CF₃, —OH, —NO₂, —C(O)NH₂, —SH,—NH₂, —SO₂, —COOH, R^(9c)-substituted or unsubstituted alkyl (e.g.,R^(9c)-substituted or unsubstituted saturated alkyl), R^(9c)-substitutedor unsubstituted heteroalkyl, R^(9c)-substituted or unsubstitutedcycloalkyl, R^(9c)-substituted or unsubstituted heterocycloalkyl,R^(9c)-substituted or unsubstituted aryl, or R^(9c)-substituted orunsubstituted heteroaryl. R^(9c) is halogen, —CN, —CF₃, —OH, —NO₂,—C(O)NH₂, —SH, —NH₂, —SO₂, —COOH, unsubstituted alkyl (e.g.,unsubstituted saturated alkyl), unsubstituted heteroalkyl, unsubstitutedcycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, orunsubstituted heteroaryl.

In one embodiment of Formulae (I), (II), (III) or (IV), R⁴ isunsubstituted C₁-C₁₀ alkyl (e.g., unsubstituted C₁-C₁₀ saturated alkyl),or unsubstituted C₃-C₈ cycloalkyl. In other embodiments, R⁴ isunsubstituted C₁-C₁₀ alkyl (e.g., unsubstituted C₁-C₁₀ saturated alkyl).In other embodiments, R⁴ is unsubstituted C₁-C₅ alkyl (e.g.,unsubstituted C₁-C₅ saturated alkyl).

In some embodiments of Formulae (I), (II), (III) or (IV), R^(9a) ishalogen, —CN, —CF₃, —OH, —NO₂, —C(O)NH₂, —SH, —NH₂, —SO₂, —COOH,R^(9b)-substituted or unsubstituted C₁-C₁₀ alkyl (e.g.,R^(9b)-substituted or unsubstituted C₁-C₁₀ saturated alkyl),R^(9b)-substituted or unsubstituted 2 to 10 membered heteroalkyl,R^(9b)-substituted or unsubstituted C₃-C₈ cycloalkyl, R^(9b)-substitutedor unsubstituted 3 to 8 membered heterocycloalkyl, R^(9b)-substituted orunsubstituted aryl, or R^(9b)-substituted or unsubstituted 5-6 memberedheteroaryl. In some embodiments, R^(9b) is halogen, —CN, —CF₃, —OH,—NO₂, —C(O)NH₂, —SH, —NH₂, —SO₂, —COOH, R^(9c)-substituted orunsubstituted C₁-C₁₀ alkyl (e.g., R^(9c)-substituted or unsubstitutedC₁-C₁₀ saturated alkyl), R^(9c)-substituted or unsubstituted 2 to 10membered heteroalkyl, R^(9c)-substituted or unsubstituted C₃-C₈cycloalkyl, R^(9c)-substituted or unsubstituted 3 to 8 memberedheterocycloalkyl, R^(9c)-substituted or unsubstituted aryl, orR^(9c)-substituted or unsubstituted 5-6 membered heteroaryl. In someembodiments, R^(9c) is halogen, —CN, —CF₃, —OH, —NO₂, —C(O)NH₂, —SH,—NH₂, —SO₂, —COOH, unsubstituted C₁-C₁₀ alkyl (e.g. unsubstituted C₁-C₁₀saturated alkyl), unsubstituted 2 to 10 membered heteroalkyl,unsubstituted C₃-C₈ cycloalkyl, unsubstituted 3 to 8 memberedheterocycloalkyl, unsubstituted aryl, or unsubstituted 5-6 memberedheteroaryl.

In some embodiments of Formulae (I), (II), (III) or (IV), R^(9a) isR^(9b)-substituted or unsubstituted C₁-C₁₀ alkyl (e.g.R^(9b)-substituted or unsubstituted C₁-C₁₀ saturated alkyl),R^(9b)-substituted or unsubstituted C₃-C₈ cycloalkyl, orR^(9b)-substituted or unsubstituted aryl. In some embodiments, R^(9b) isR^(9c)-substituted or unsubstituted C₁-C₁₀ alkyl (e.g.R^(9c)-substituted or unsubstituted C₁-C₁₀ saturated alkyl),R^(9c)-substituted or unsubstituted C₃-C₈ cycloalkyl, orR^(9c)-substituted or unsubstituted aryl. In some embodiments, R^(9c) isunsubstituted C₁-C₁₀ alkyl (e.g., unsubstituted C₁-C₁₀ saturated alkyl),unsubstituted C₃-C₈ cycloalkyl, or unsubstituted aryl.

In some embodiments of Formulae (I), (II), (III) or (IV), R^(9a) isunsubstituted C₁-C₁₀ alkyl (e.g., unsubstituted C₁-C₁₀ saturated alkyl),unsubstituted C₃-C₈ cycloalkyl, or unsubstituted aryl. In someembodiments, R^(9a) is unsubstituted C₁-C₁₀ alkyl (e.g., unsubstitutedC₁ to C₁₀ saturated alkyl). In some embodiments, R^(9a) is unsubstitutedC₁-C₄ alkyl (e.g., unsubstituted C₁ to C₄ saturated alkyl). In someembodiments, R^(9a) is unsubstituted C₃-C₈ cycloalkyl. In someembodiments, R^(9a) is unsubstituted aryl (e.g., phenyl).

In one embodiment of Formulae (I), (II), (III) or (IV), R⁵ is hydrogen.In other embodiments, R⁵ is substituted or unsubstituted C₁-C₁₀ alkyl(e.g., substituted or unsubstituted C₁-C₁₀ saturated alkyl), orsubstituted or unsubstituted C₃-C₈ cycloalkyl. In one embodiment, R⁵ issubstituted or unsubstituted C₁-C₆ alkyl (e.g., substituted orunsubstituted C₁-C₆ saturated alkyl). In one embodiment, R⁵ issubstituted or unsubstituted C₁-C₃ alkyl (e.g., substituted orunsubstituted C₁-C₃ saturated alkyl). In one embodiment, R⁵ issubstituted or unsubstituted C₂ alkyl (e.g., substituted orunsubstituted C₁-C₂ saturated alkyl). In one embodiment, R⁵ is ethyl. Inone embodiment, R⁵ is substituted or unsubstituted C₃-C₈ cycloalkyl.

In one embodiment of Formulae (I), (II), (III) or (IV), R⁵ isR^(10a)-substituted or unsubstituted C₁-C₁₀ alkyl (e.g.,R^(10a)-substituted or unsubstituted C₁-C₁₀ saturated alkyl), orR^(10a)-substituted or unsubstituted C₃-C₈ cycloalkyl. R^(10a) ishalogen, —CN, —CF₃, —OH, —NO₂, —C(O)NH₂, —SH, —NH₂, —SO₂, —COOH,R^(10b)-substituted or unsubstituted alkyl (e.g., R^(10b)-substituted orunsubstituted C₁-C₁₀ saturated alkyl), R^(10b)-substituted orunsubstituted heteroalkyl, R^(10b)-substituted or unsubstitutedcycloalkyl, R^(10b)-substituted or unsubstituted heterocycloalkyl,R^(10b)-substituted or unsubstituted aryl, or R^(10b)-substituted orunsubstituted heteroaryl. R^(10b) is halogen, —CN, —CF₃, —OH, —NO₂,—C(O)NH₂, —SH, —NH₂, —SO₂, —COOH, R^(10c)-substituted or unsubstitutedalkyl (e.g., R^(10c)-substituted or unsubstituted C₁-C₁₀ saturatedalkyl), R^(10c)-substituted or unsubstituted heteroalkyl,R^(10c)-substituted or unsubstituted cycloalkyl, R^(10c)-substituted orunsubstituted heterocycloalkyl, R^(10c)-substituted or unsubstitutedaryl, or R^(10c)-substituted or unsubstituted heteroaryl. R^(10c) ishalogen, —CN, —CF₃, —OH, —NO₂, —C(O)NH₂, —SH, —NH₂, —SO₂, —COOH,unsubstituted alkyl (e.g., unsubstituted saturated alkyl), unsubstitutedheteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl,unsubstituted aryl, or unsubstituted heteroaryl.

In one embodiment of Formulae (I), (II), (III) or (IV), R⁵ isunsubstituted C₁-C₁₀ alkyl (e.g., unsubstituted C₁-C₁₀ saturated alkyl),or unsubstituted C₃-C₈ cycloalkyl. In other embodiments, R⁵ isunsubstituted C₁-C₁₀ alkyl (e.g., unsubstituted C₁-C₁₀ saturated alkyl).In other embodiments, R⁵ is unsubstituted C₁-C₅ alkyl (e.g.,unsubstituted C₁-C₅ saturated alkyl).

In some embodiments of Formulae (I), (II), (III) or (IV), R^(10a) ishalogen, —CN, —CF₃, —OH, —NO₂, —C(O)NH₂, —SH, —NH₂, —SO₂, —COOH,R^(10b)-substituted or unsubstituted C₁-C₁₀ alkyl (e.g.,R^(10b)-substituted or unsubstituted C₁-C₁₀ saturated alkyl),R^(10b)-substituted or unsubstituted 2 to 10 membered heteroalkyl,R^(10b)-substituted or unsubstituted C₃-C₈ cycloalkyl,R^(10b)-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R^(10b)-substituted or unsubstituted aryl, or R^(10b)-substituted orunsubstituted 5-6 membered heteroaryl. In some embodiments, R^(10b) ishalogen, —CN, —CF₃, —OH, —NO₂, —C(O)NH₂, —SH, —NH₂, —SO₂, —COOH,R^(10c)-substituted or unsubstituted C₁-C₁₀ alkyl (e.g.,R^(10c)-substituted or unsubstituted C₁-C₁₀ saturated alkyl),R^(10c)-substituted or unsubstituted 2 to 10 membered heteroalkyl,R^(10c)-substituted or unsubstituted C₃-C₈ cycloalkyl,R^(10c)-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R^(10c)-substituted or unsubstituted aryl, or R^(10c)-substituted orunsubstituted 5-6 membered heteroaryl. In some embodiments, R^(10c) ishalogen, —CN, —CF₃, —OH, —NO₂, —C(O)NH₂, —SH, —NH₂, —SO₂, —COOH,unsubstituted C₁-C₁₀ alkyl (e.g., unsubstituted C₁-C₁₀ saturated alkyl),unsubstituted 2 to 10 membered heteroalkyl, unsubstituted C₃-C₈cycloalkyl, unsubstituted 3 to 8 membered heterocycloalkyl,unsubstituted aryl, or unsubstituted 5-6 membered heteroaryl.

In some embodiments of Formulae (I), (II), (III) or (IV), R^(10a) isR^(10b)-substituted or unsubstituted C₁-C₁₀ alkyl (e.g.,R^(10b)-substituted or unsubstituted C₁-C₁₀ saturated alkyl),R^(10b)-substituted or unsubstituted C₃-C₈ cycloalkyl, orR^(10b)-substituted or unsubstituted aryl. In some embodiments, R^(10b)is R^(10c)-substituted or unsubstituted C₁-C₁₀ alkyl (e.g.,R^(10c)-substituted or unsubstituted C₁-C₁₀ saturated alkyl),R^(10c)-substituted or unsubstituted C₃-C₈ cycloalkyl orR^(10c)-substituted or unsubstituted aryl. In some embodiments, R^(10c)is unsubstituted C₁-C₁₀ alkyl (e.g., unsubstituted C₁-C₁₀ saturatedalkyl), unsubstituted C₃-C₈ cycloalkyl, or unsubstituted aryl.

In some embodiments of Formulae (I), (II), (III) or (IV), R^(10a) isunsubstituted C₁-C₁₀ alkyl (e.g., unsubstituted C₁-C₁₀ saturated alkyl),unsubstituted C₃-C₈ cycloalkyl, or unsubstituted aryl. In someembodiments, R^(10a) is unsubstituted C₁-C₁₀ alkyl (e.g., unsubstitutedC₁ to C₁₀ saturated alkyl). In some embodiments, R^(10a) isunsubstituted C₁-C₄ alkyl (e.g., unsubstituted C₁ to C₄ saturatedalkyl). In some embodiments, R^(10a) is unsubstituted C₃-C₈ cycloalkyl.In some embodiments, R^(10a) is unsubstituted aryl (e.g., phenyl).

Further to any of Formulae (I), (II), (III) or (IV), in some embodimentsone of R⁴ or R⁵ is hydrogen.

Further to any of Formulae (I), (II), (III) or (IV), in some embodimentsa substituent is a size-limited substituent. For example withoutlimitation, in some embodiments each substituted or unsubstituted alkylmay be a substituted or unsubstituted C₁-C₂₀, C₁-C₁₀, C₁-C₆, or even C₁alkyl. In some embodiments each substituted or unsubstituted heteroalkylmay be a substituted or unsubstituted 2-20 membered, 2-10 membered, or2-6 membered heteroalkyl. In some embodiments, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈, C₄-C₈,C₅-C₇ cycloalkyl. In some embodiments, each substituted or unsubstitutedheterocycloalkyl is a substituted or unsubstituted 3-8 membered, 4-8membered, or 3-6 membered heterocycloalkyl. In some embodiments, eachsubstituted or unsubstituted heteroaryl is a substituted orunsubstituted 4-14 membered, 4-10 membered, 5-8 membered, 4-6 membered,5-6 membered, or 6-membered heteroaryl. In some embodiments, eachsubstituted or unsubstituted aryl is a substituted or unsubstitutedC₄-C₁₄, C₄-C₁₀, C₆-C₁₀, C₅-C₈, C₅-C₆, or C₆ aryl (phenyl).

In some embodiments of Formula (II), R¹ is R^(1a)C(O)—, R^(1a) isunsubstituted C₁-C₄ saturated alkyl or unsubstituted aryl (e.g.,phenyl), R⁴ is unsubstituted C₁-C₄ saturated alkyl and R⁵ is hydrogen.In some embodiments of Formula (II), R¹ is R^(1a)C(O)—, R^(1a) isunsubstituted C₁-C₄ saturated alkyl, R⁴ is unsubstituted C₁-C₄ saturatedalkyl and R⁵ is hydrogen. In some embodiments of Formula (II), R¹ isR^(1a)C(O)—, R^(1a) is unsubstituted C₁-C₃ saturated alkyl, R⁴ isunsubstituted C₁-C₃ saturated alkyl and R⁵ is hydrogen. In someembodiments of Formula (II), R¹ is R^(1a)C(O)—, R^(1a) is methyl, ethyl,propyl or isopropyl, R⁴ is unsubstituted ethyl or methyl and R⁵ ishydrogen. In some embodiments of Formula (II), R¹ is R^(1a)C(O)—, R^(1a)is phenyl, R⁴ is unsubstituted ethyl or methyl and R⁵ is hydrogen.

In some embodiments of Formula (III), R² is R^(2a)C(O)—, R^(2a) isunsubstituted C₁-C₅ saturated alkyl or unsubstituted aryl (e.g.,phenyl), R⁴ is unsubstituted C₁-C₄ saturated alkyl and R⁵ is hydrogen.In some embodiments of Formula (III), R² is R^(2a)C(O)—, R^(2a) isunsubstituted C₁-C₄ saturated alkyl or unsubstituted aryl (e.g.,phenyl), R⁴ is unsubstituted C₁-C₃ saturated alkyl (e.g., methyl orethyl) and R⁵ is hydrogen. In some embodiments of Formula (III), R² isR^(2a)C(O)—, R^(2a) is methyl, ethyl, propyl, isopropyl or unsubstitutedphenyl, R⁴ is unsubstituted ethyl or methyl, and R⁵ is hydrogen. In someembodiments of Formula (III), R² is R^(2a)C(O)—, R^(2a) is methyl,ethyl, propyl, or isopropyl, R⁴ is unsubstituted ethyl or methyl, and R⁵is hydrogen. In some embodiments of Formula (III), R² is R^(2a)C(O)—,R^(2a) is unsubstituted phenyl, R⁴ is unsubstituted ethyl or methyl, andR⁵ is hydrogen.

In some embodiments of Formula (IV), R³ is R^(3a)C(O)—, R^(3a) isunsubstituted C₁-C₅ saturated alkyl or unsubstituted aryl (e.g.,phenyl), R⁴ is unsubstituted C₁-C₄ saturated alkyl, and R⁵ is hydrogen.In some embodiments of Formula (IV), R³ is R^(3a)C(O)—, R^(3a) isunsubstituted C₁-C₅ saturated alkyl, R⁴ is unsubstituted C₁-C₄ saturatedalkyl, and R⁵ is hydrogen. In some embodiments of Formula (IV), R³ isR^(3a)C(O)—, R^(3a) is unsubstituted C₁-C₄ saturated alkyl, R⁴ isunsubstituted C₁-C₃ saturated alkyl, and R⁵ is hydrogen. In someembodiments of Formula (IV), R³ is R^(3a)C(O)—, R^(3a) is methyl, ethylpropyl or isopropyl, R⁴ is unsubstituted ethyl or methyl, and R⁵ ishydrogen. In some embodiments of Formula (IV), R³ is R^(3a)C(O)—, R^(3a)is unsubstituted phenyl, R⁴ is unsubstituted ethyl or methyl, and R⁵ ishydrogen.

Embodiments of the compound of Formula (II) include compounds withstructure of one of Formulae (IIa)-(IIc) following:

Embodiments of the compound with structure of Formula (III) includecompounds with structure of one of Formulae (IIIa)-(IIId) following:

Embodiments of the compound with structure of Formula (IV) includecompounds with structure of one of Formulae (IVa)-(IVc) following:

In one embodiment, the compound has the structure of Formula (IVa). Inone embodiment, the compound has the structure of Formula (IIIb). In oneembodiment, the compound has the structure of Formula (IVb).

In some embodiments, the compounds of Formulae (I), (II), (III) or (IV)have the stereochemistry configuration set forth in Formulae (IIa),(IIb), (IIc), (IIIa), (IIIb), (IIIc), (IIId), (IVa), (IVb), and (IVc).

It is understood that a compound described herein, e.g., a compound withstructure of any of Formulae (I), (II), (III), (IV), (IIa), (IIb),(IIc), (IIIa), (IIIb), (IIIc), (IIId), (IVa), (IVb), or (IVc) orderivative, isomer or enantiomer thereof, can be provided, whereapplicable, as a pharmaceutically acceptable salt as defined herein,where the compound admits to formation of a pharmaceutically acceptablesalt.

III. Pharmaceutical Compositions

In another aspect, there is provided a pharmaceutical compositionincluding a pharmaceutically acceptable excipient and a compoundprovided herein (e.g., a compound with structure of Formula (I), (II),(III), (IV), (IIa), (IIb), (IIc), (IIIa), (IIIb), (IIIc), (IIId), (IVa),(IVb), or (IVc) or derivative, isomer or enantiomer thereof andincluding embodiments thereof).

In one embodiment, the compound has the structure of one of Formulae(IVa), (IIIb) or (IVb). In one embodiment, the compound has thestructure of Formula (IVb).

In one embodiment, the pharmaceutical composition is a solution,emulsion, gel or foam. In one embodiment, the pharmaceutical compositionis a solution. In one embodiment, the pharmaceutical composition is anemulsion. In one embodiment, the pharmaceutical composition is a gel. Inone embodiment, the pharmaceutical composition is a foam.

In one embodiment, the pharmaceutical composition is a topicalpharmaceutical composition. In one embodiment, the pharmaceuticalcomposition is a topical epidermal pharmaceutical composition.

It is understood that the compound within the pharmaceutical compositiondescribed herein (e.g., a compound with structure of Formula (I), (II),(III), (IV), (IIa), (IIb), (IIc), (IIIa), (IIIb), (IIIc), (IIId), (IVa),(IVb), or (IVc) or derivative, isomer or enantiomer thereof andincluding embodiments thereof) can be provided, where applicable, as apharmaceutically acceptable salt as defined herein, where the compoundadmits to formation of a pharmaceutically acceptable salt.

A. Formulations

The compounds and pharmaceutical compositions disclosed herein can beprepared and administered in a variety of forms including solution,emulsion, gel or foam. Accordingly, pharmaceutical compositionscontemplated herein include a pharmaceutically acceptable carrier orexcipient and one or more compounds described herein. “Solution” refersin the customary sense to a liquid pharmaceutical composition in which acompound (e.g., a compound described herein), is at least partiallydissolved, preferably fully dissolved, and which can be administered asa liquid. “Emulsion” refers in the customary sense to a mixture of twoor more immiscible liquids, one compound (e.g., a compound describedherein or solution thereof) being dispersed through the other compound(e.g., a carrier as described herein). “Gel” refers in the customarysense to a highly viscous solution, emulsion, or colloidal suspension ofa compound within a continuous fluid phase resulting in a viscoussemirigid fluid. “Colloid” refers in the customary sense to acomposition which includes a continuous medium throughout which aredistributed small particles which do not settle under the influence ofgravity. “Foam” refers in the customary sense to a composition whichincludes a continuous medium (i.e., solution, emulsion, gel and thelike) through which gas (e.g., air) is dispersed.

Pharmaceutical compositions contemplated herein may be prepared bycombining a therapeutically effective amount of at least one compound asdescribed herein as an active ingredient in combination with one or moreconventional pharmaceutically acceptable excipients, and by preparationof unit dosage forms suitable for topical use. The therapeuticallyefficient amount typically is between about 0.0001 and about 5% (w/v),preferably about 0.001 to about 1.0% (w/v) in liquid formulations whichinclude solutions, emulsions, gels and foams. Pharmaceutical admixturessuitable for use in the present invention include those described, forexample, in PHARMACEUTICAL SCIENCES (17th Ed., Mack Pub. Co., Easton,Pa.) and WO 96/05309, the teachings of both of which are herebyincorporated by reference.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Some compounds may have limited solubility in water and therefore mayrequire a surfactant or other appropriate co-solvent in the composition.Such co-solvents include: Polysorbate 20, 60, and 80; Pluronic F-68,F-84, and P-103; cyclodextrin; and polyoxyl 35 castor oil. Suchco-solvents are typically employed at a level between about 0.01% andabout 2% by weight.

Viscosity greater than that of simple aqueous solutions may be desirableto decrease variability in dispensing the formulations, to decreasephysical separation of components of a suspension or emulsion offormulation, and/or otherwise to improve the formulation. Such viscositybuilding agents include, for example, polyvinyl alcohol, polyvinylpyrrolidone, methyl cellulose, hydroxy propyl methylcellulose,hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propylcellulose, chondroitin sulfate and salts thereof, hyaluronic acid andsalts thereof, and combinations of the foregoing. Such agents aretypically employed at a level between about 0.01% and about 2% byweight.

The compositions of the present invention may additionally includecomponents to provide sustained release and/or comfort. Such componentsinclude high molecular weight, anionic mucomimetic polymers, gellingpolysaccharides, and finely-divided drug carrier substrates. Thesecomponents are discussed in greater detail in U.S. Pat. Nos. 4,911,920;5,403,841; 5,212,162; and 4,861,760. The entire contents of thesepatents are incorporated herein by reference in their entirety for allpurposes. US Patent application publication No. US 2011-0124736 A1, alsocorresponding to U.S. patent application Ser. No. 12/940,711, is herebyincorporated by reference in its entirety.

For ophthalmic application, preferably solutions are prepared using aphysiological saline solution as a major vehicle. The pH of suchophthalmic solutions should preferably be maintained between 4.5 and 8.0with an appropriate buffer system, a neutral pH being preferred but notessential. The formulations may also contain conventional,pharmaceutically acceptable preservatives, stabilizers and surfactants.

Various buffers and means for adjusting pH may be used so long as theresulting preparation is ophthalmically acceptable. Accordingly, buffersinclude acetate buffers, citrate buffers, phosphate buffers and boratebuffers. Acids or bases may be used to adjust the pH of theseformulations as needed.

Preferred preservatives that may be used in the pharmaceuticalcompositions of the present invention include, but are not limited to,benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetateand phenylmercuric nitrate. A preferred surfactant is, for example,Tween 80. Likewise, various preferred vehicles may be used in theophthalmic preparations of the present invention. These vehiclesinclude, but are not limited to, polyvinyl alcohol, povidone,hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose,hydroxyethyl cellulose cyclodextrin and purified water.

Tonicity adjustors may be added as needed or convenient. They include,but are not limited to, salts, particularly sodium chloride, potassiumchloride, mannitol and glycerin, or any other suitable ophthalmicallyacceptable tonicity adjustor.

An ophthalmically acceptable antioxidant for use in the presentinvention includes, but is not limited to, sodium metabisulfite, sodiumthiosulfate, acetylcysteine, butylated hydroxyanisole and butylatedhydroxytoluene.

Other excipient components which may be included in the ophthalmicpreparations are chelating agents. The preferred chelating agent isedentate disodium, although other chelating agents may also be used inplace of or in conjunction with it.

The ophthalmic formulations of the present invention are convenientlypackaged in forms suitable for metered application, such as incontainers equipped with a brush, to facilitate application to thepalpebra. In one embodiment, an application brush is disposed within aunit dose vial. Vials suitable for unit dose application are usuallymade of suitable inert, non-toxic plastic material, and generallycontain between about 0.5 and about 15 ml solution, emulsion, gel orfoam. One package may contain one or more unit doses.

Preservative-free solutions are often formulated in non-resealablecontainers containing up to about ten, preferably up to about five unitsdoses, where a typical unit dose is from one to about 8 drops,preferably one to about 3 drops.

For topical use on the eyelids or eyebrows, the active compounds can beformulated in aqueous solutions, creams, ointments or oils exhibitingphysiologically acceptable osmolarity by addition of pharmacologicallyacceptable buffers and salts. Such formulations may or may not,depending on the dispenser, contain preservatives such as benzalkoniumchloride, chlorhexidine, chlorobutanol, parahydroxybenzoic acids andphenylmercuric salts such as nitrate, chloride, acetate, and borate, orantioxidants, as well as additives like EDTA, sorbitol, boric acid etc.as additives. Furthermore, particularly aqueous solutions may containviscosity increasing agents such as polysaccharides, e.g.,methylcellulose, mucopolysaccharides, e.g., hyaluronic acid andchondroitin sulfate, or polyalcohol, e.g., polyvinylalcohol. Variousslow releasing gels and matrices may also be employed as well as solubleand insoluble ocular inserts, for instance, based on substances formingin-situ gels.

For topical use on the skin and the scalp, the compound can beadvantageously formulated using ointments, creams, liniments or patchesas a carrier of the active ingredient. Also, these formulations may ormay not contain preservatives, depending on the dispenser and nature ofuse. Such preservatives include those mentioned above, and methyl-,propyl-, or butyl-parahydroxybenzoic acid, betain, chlorhexidine,benzalkonium chloride, and the like. Various matrices for slow releasedelivery may also be used.

Typically, the compounds are applied repeatedly for a sustained periodof time topically on the part of the body to be treated, for example,the eyelids, eyebrows, body or scalp. The preferred dosage regimen willgenerally involve regular administration for a period of treatment of atleast one month, more preferably at least three months, and mostpreferably at least six months. The regular administration can be 1, 2,3, 4 or even more times per day.

Formulations for use in the methods and pharmaceutical compositionsdisclosed herein include Formulation A, provided in Table 1 following.The term “active component” refers to bimatoprost or a compound asdescribed herein (e.g., a compound with structure of Formula (I), (II),(III), (IV), (IIa), (IIb), (IIc), (IIIa), (IIIb), (IIIc), (IIId), (IVa),(IVb), or (IVc) or derivative, isomer or enantiomer thereof andincluding embodiments thereof). As customary in the art, the term “q.s.”(i.e., quantum satis) refers to as much as is enough. For example,“water q.s. to 100%” refers to sufficient water to bring the formulationto 100%.

TABLE 1 Formulation A Ingredient Amount Active component (% w/w) 0.03Glycerin (% w/w) 2.0 Propylene Glycol (% w/w) 10.0 Diethylene GlycolMonoethyl Ether (% w/w) 10.0 Ethyl Alcohol (% w/w) 30.0 Carbomer Ultrez10 (% w/w) 0.15 Triethanolamine (% w/w) 0.16 Purified Water q.s. to 100%pH ~7

Additional formulations for use in the methods and pharmaceuticalcompositions disclosed herein include formulations exemplified in Tables2 and 3 following, wherein the amount of each component (i.e., % w/w) isincluded within the indicated range.

TABLE 2 Exemplary Formulations Ingredient Range (% w/w) Active component0.001-3.00  Glycerin 1.0-4.0 Propylene Glycol  5.0-15.0 DiethyleneGlycol Monoethyl Ether  5.0-15.0 Ethyl Alcohol 25.0-35.0 Carbomer Ultrez10 0.05-0.30 Triethanolamine 0.05-0.30 Purified Water q.s. to 100%

TABLE 3 Exemplary Formulations Ingredient Range (% w/w) Active component0.01-0.1  Glycerin 0.001-4.0   Propylene Glycol 0.5-20.0 DiethyleneGlycol Monoethyl Ether 0.5-20.0 Ethyl Alcohol 0.5-45.0 Carbomer Ultrez10 0.1-0.30 Triethanolamine 0.1-0.32 Purified Water q.s. to 100%

B. Effective Dosages

Pharmaceutical compositions provided herein include compositions whereinthe active ingredient (e.g., a compound with structure of Formula (I),(II), (III), (IV), (IIa), (IIb), (IIc), (IIIa), (IIIb), (IIIc), (IIId),(IVa), (IVb), or (IVc) or derivative, isomer or enantiomer thereof andincluding embodiments thereof) is contained in a therapeuticallyeffective amount. The actual amount effective for a particularapplication will depend, inter alia, on the disease, disorder orcondition being treated.

The dosage and frequency (single or multiple doses) of compoundadministered can vary depending upon a variety of factors, includingroute of administration; size, age, sex, health, body weight, body massindex, and diet of the recipient; nature and extent of symptoms of thedisease, disorder or condition being treated (e.g., the degree of hairloss); presence of other diseases or other health-related problems; kindof concurrent treatment; and complications from any disease or treatmentregimen. Other therapeutic regimens or agents can be used in conjunctionwith the methods and compounds of the invention.

Therapeutically effective amounts for use in humans may be determinedfrom animal models. For example, a dose for humans can be formulated toachieve a concentration that has been found to be effective in animals.The dosage in humans can be adjusted by monitoring piliation andadjusting the dosage upwards or downwards, as described herein.

Dosages may be varied depending upon the requirements of the subject andthe compound being employed. The dose administered to a subject, in thecontext of the present invention, should be sufficient to effect abeneficial therapeutic response in the patient over time. The size ofthe dose also will be determined by the existence, nature, and extent ofany adverse side effects. Generally, treatment is initiated with smallerdosages, which are less than the optimum dose of the compound.Thereafter, the dosage is increased by small increments until theoptimum effect under circumstances is reached.

Dosage amounts and intervals can be adjusted individually to providelevels of the administered compound effective for the particularclinical indication being treated. This will provide a therapeuticregimen that is commensurate with the severity of the individual'sdisease state.

Utilizing the teachings provided herein, an effective prophylactic ortherapeutic treatment regimen can be planned that does not causesubstantial toxicity and yet is entirely effective to treat the clinicalsymptoms demonstrated by the particular patient. This planning shouldinvolve the careful choice of active compound by considering factorssuch as compound potency, relative bioavailability, patient body weight,presence and severity of adverse side effects, preferred mode ofadministration, and the toxicity profile of the selected agent.

Depending on the actual formulation and compound to be used, variousamounts of the drug and different dose regimens may be employed. In oneembodiment, the daily amount of compound for treatment of the palpebrais about 0.1 ng to about 100 mg per eyelid.

In some embodiments, for topical use on the skin and the scalp, the doseto be applied is in the range of about 0.1 ng to about 100 mg per day,more preferably about 1 ng to about 10 mg per day, and most preferablyabout 10 ng to about 1 mg per day depending on the compound and theformulation. To achieve the daily amount of medication depending on theformulation, the compound may be administered once or several timesdaily with or without antioxidants.

In some embodiments, an amount of the active compound in apharmaceutical composition, e.g., a compound disclosed herein in apharmaceutical composition disclosed herein, is about 1×10⁻⁷ to 50%(w/w), about 0.001 to 50% (w/w), about 0.01 to 50% (w/w), about 0.1 to50% (w/w), or about 1 to 50% (w/w). In some embodiments, the amount ofthe active compound in a pharmaceutical composition is about 0.001%,0.005%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%,0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%,1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 3.0%, 4.0% and 5.0% w/w.

In some embodiments, an effective amount, e.g., a therapeuticallyeffective amount, of the active compound in a pharmaceutical compositionis afforded at a concentration of about 1×10⁻⁷ to 50% (w/w), about 0.001to 50% (w/w), about 0.01 to 50% (w/w), about 0.1 to 50% (w/w), or about1 to 50% (w/w). In some embodiments, the therapeutically effectiveamount of the active compound in a pharmaceutical composition is about0.001%, 0.005%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%,0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9% and 1.0%,1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 3.0%, 4.0%and 5.0% w/w.

C. Toxicity

The ratio between toxicity and therapeutic effect for a particularcompound is its therapeutic index and can be expressed as the ratiobetween LD₅₀ (the amount of compound lethal in 50% of the population)and ED₅₀ (the amount of compound effective in 50% of the population).Compounds that exhibit high therapeutic indices are preferred.Therapeutic index data obtained from cell culture assays and/or animalstudies can be used in formulating a range of dosages for use in humans.The dosage of such compounds preferably lies within a range of plasmaconcentrations that include the ED₅₀ with little or no toxicity. Thedosage may vary within this range depending upon the dosage formemployed and the route of administration utilized. See, e.g., Fingl etal., In: THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, Ch. 1, p. 1, 1975.The exact formulation, route of administration, and dosage can be chosenby the individual physician in view of the patient's condition and theparticular method in which the compound is used.

IV. Methods of Use

In another aspect, there is provided a method for inducing hair growth(e.g., piliation). The method includes administering to a subject inneed thereof a therapeutically effective amount of a compound providedherein (e.g., a compound with structure of Formula (I), (II), (III),(IV), (IIa), (IIb), (IIc), (IIIa), (IIIb), (IIIc), (IIId), (IVa), (IVb),or (IVc) or derivative, isomer or enantiomer thereof and includingembodiments thereof). The compound may be provided as part of apharmaceutical composition as described herein.

In one embodiment, the subject suffers from alopecia such that themethod of inducing hair growth is a method for treating alopecia. In oneembodiment, the subject is in need of hair growth of the cilia, thesupercilium, scalp pili or body pili such that the method of inducinghair growth is a method for inducing growth of the cilia, thesupercilium, scalp pili or body pili or the subject, respectively. Inone embodiment, the subject is in need of hair growth of the cilia. Inone embodiment, the subject is in need of hair growth of thesupercilium. In one embodiment, the subject is in need of hair growth ofscalp pili. In one embodiment, the subject is in need of hair growth ofbody pili.

In one embodiment, the administering is topical administering. In oneembodiment, the administering is topical epidermal administering.

In one embodiment, the administering is topical palpebra administering,topical supercilium administering, topical scalp administering, ortopical body administering. In one embodiment, the administering istopical palpebra administering. In one embodiment, the administering istopical supercilium administering. In one embodiment, the administeringis topical scalp administering. In one embodiment, the administering istopical body administering.

In one embodiment, the administering is topical scalp administering. Ina further embodiment, the composition is a foam.

In one embodiment, the administering is topical palpebra administering.In a further embodiment, the composition is administered from a unitdose vial (e.g., by an application brush disposed within a unit dosevial).

In another aspect, there is provided a method for treating aninflammatory skin disease or disorder. The method includes administeringto a subject in need thereof a therapeutically effective amount of acompound provided herein (e.g., a compound with structure of Formula(I), (II), (III), (IV), (IIa), (IIb), (IIc), (IIIa), (IIIb), (IIIc),(IIId), (IVa), (IVb), or (IVc) or derivative, isomer or enantiomerthereof and including embodiments thereof). The compound may be providedas part of a pharmaceutical composition as described herein.

In one embodiment, the subject suffers from rosacea or redness fromrosacea. Thus, the method of treating an inflammatory skin disease, insome embodiments, is a method of treating rosacea or redness fromrosacea.

In another aspect, there is provided a method for reducing local adiposedeposits. The method includes administering to a subject in need thereofa therapeutically effective amount of a compound provided herein (e.g.,a compound with structure of Formula (I), (II), (III), (IV), (IIa),(IIb), (IIc), (IIIa), (IIIb), (IIIc), (IIId), (IVa), (IVb), or (IVc) orderivative, isomer or enantiomer thereof and including embodimentsthereof). The compound may be provided as part of a pharmaceuticalcomposition as described herein. The term “local adipose deposit” refersto an adipose (i.e., fat) deposit in a subject which is localized in itsextent. In some embodiments, the extent of the greatest dimension of alocal adipose deposit is about 1 cm, 2 cm, 3 cm, 4 cm, 5 cm, 6 cm, 7 cm,8 cm, 9 cm, 10 cm, 20 cm, or even greater. The term “reducing” in thecontext of reducing adipose deposits (e.g., local adipose deposits)refers to lowering the fat content within such deposits and reducing themass of the adipose deposit.

In another aspect, there is provided a method for lowering intraocularpressure. The method includes administering to a subject in need thereofa therapeutically effective amount of a compound provided herein (e.g.,a compound with structure of Formula (I), (II), (III), (IV), (IIa),(IIb), (IIc), (IIIa), (IIIb), (IIIc), (IIId), (IVa), (IVb), or (IVc) orderivative, isomer or enantiomer thereof and including embodimentsthereof). The compound may be provided as part of a pharmaceuticalcomposition as described herein.

In another aspect, there is provided a method of treating glaucoma. Themethod includes administering to a subject in need thereof atherapeutically effective amount of a compound provided herein (e.g., acompound with structure of Formula (I), (II), (III), (IV), (IIa), (IIb),(IIc), (IIIa), (IIIb), (IIIc), (IIId), (IVa), (IVb), or (IVc) orderivative, isomer or enantiomer thereof and including embodimentsthereof). The compound may be provided as part of a pharmaceuticalcomposition as described herein.

In another aspect, there is provided a method of providing bimatoprosttherapy. The method includes administering to a subject in need thereofa therapeutically effective amount of a compound provided herein (e.g.,a compound with structure of Formula (I), (II), (III), (IV), (IIa),(IIb), (IIc), (IIIa), (IIIb), (IIIc), (IIId), (IVa), (IVb), or (IVc) orderivative, isomer or enantiomer thereof and including embodimentsthereof). The compound may be provided as part of a pharmaceuticalcomposition as described herein.

In some embodiments, the subject is a mammalian subject. In otherembodiments the subject is a domesticated animal such as a domesticatedmammal. In other embodiments, the subject is a human subject (e.g., apatient).

Compounds useful in the methods provided here include those withstructure of Formula (I) and embodiments thereof (e.g., a compound withstructure of Formula (I), (II), (III), (IV), (IIa), (IIb), (IIc),(IIIa), (IIIb), (IIIc), (IIId), (IVa), (IVb), or (IVc) or derivative,isomer or enantiomer thereof and including embodiments thereof).

In one embodiment of compounds useful in the methods provided herein,R^(1a), R^(2a) and R^(3a) are independently substituted or unsubstitutedC₁-C₆ alkyl. In one embodiment, R^(1a), R^(2a) and R^(3a) areindependently substituted or unsubstituted C₁-C₃ alkyl. In oneembodiment, R^(1a), R^(2a) and R^(3a) are independently substituted orunsubstituted C₁ alkyl. In one embodiment, R^(1a), R^(2a) and R^(3a) areindependently methyl.

In one embodiment, R^(1a), R^(2a) and R^(3a) are independentlysubstituted or unsubstituted C₃-C₈ cycloalkyl.

In one embodiment, R^(1a), R^(2a) and R^(3a) are independentlysubstituted or unsubstituted aryl. In one embodiment, R^(1a), R^(2a) andR^(3a) are independently aryl. In one embodiment, R^(1a), R^(2a) andR^(3a) are independently phenyl.

In some embodiments, for the compounds with structure of Formula (I), atleast one of R¹, R² and R³, e.g., R¹, R², R³, each of R¹ and R², each ofR¹ and R³, each of R² and R³, or each of R¹ and R² and R³ is nothydrogen. In one embodiment, one of R¹, R² and R³ is not hydrogen. Inone embodiment, two of R¹, R² and R³ are not hydrogen. In oneembodiment, all of R¹, R² and R³ are not hydrogen.

In one embodiment, R^(1a) is R^(6a)-substituted or unsubstituted C₁-C₁₀alkyl, R^(6a)-substituted or unsubstituted C₃-C₈ cycloalkyl, orR^(6a)-substituted or unsubstituted aryl. R^(6a) is as described above.

In one embodiment, R^(2a) is R^(7a)-substituted or unsubstituted C₁-C₁₀alkyl, R^(7a)-substituted or unsubstituted C₃-C₈ cycloalkyl, orR^(7a)-substituted or unsubstituted aryl. R^(7a) is as described above.

In one embodiment, R^(3a) is R^(8a)-substituted or unsubstituted C₁-C₁₀alkyl, R^(8a)-substituted or unsubstituted C₃-C₈ cycloalkyl, orR^(8a)-substituted or unsubstituted aryl. R^(8a) is as described above.

In one embodiment, R⁴ is hydrogen. In one embodiment, R⁴ is substitutedor unsubstituted C₁-C₁₀ alkyl, or substituted or unsubstituted C₃-C₈cycloalkyl. In one embodiment, R⁴ is substituted or unsubstituted C₁-C₆alkyl. In one embodiment, R⁴ is substituted or unsubstituted C₁-C₃alkyl. In one embodiment, R⁴ is substituted or unsubstituted C₂ alkyl.In one embodiment, R⁴ is ethyl. In one embodiment, R⁴ is substituted orunsubstituted C₃-C₈ cycloalkyl.

In one embodiment, R⁴ is R^(9a)-substituted or unsubstituted C₁-C₁₀alkyl, or R^(9a)-substituted or unsubstituted C₃-C₈ cycloalkyl. R^(9a)is as described above.

In one embodiment, R⁵ is hydrogen. In one embodiment, R⁵ is substitutedor unsubstituted C₁-C₁₀ alkyl, or substituted or unsubstituted C₃-C₈cycloalkyl. In one embodiment, R⁵ is substituted or unsubstituted C₁-C₆alkyl. In one embodiment, R⁵ is substituted or unsubstituted C₁-C₃alkyl. In one embodiment, R⁵ is substituted or unsubstituted C₂ alkyl.In one embodiment, R⁵ is ethyl. In one embodiment, R⁵ is substituted orunsubstituted C₃-C₈ cycloalkyl.

In one embodiment, R⁵ is R^(10a)-substituted or unsubstituted C₁-C₁₀alkyl, or R^(10a)-substituted or unsubstituted C₃-C₈ cycloalkyl. R^(10a)is as described above.

In one embodiment, the compound with structure of Formula (I) has thestructure of one of Formulae (II), (III) or (IV), wherein R¹, R^(1a),R², R^(2a), R³, R^(3a), R⁴, R⁵, R^(6a), R^(6b), R^(6c), R^(7a), R^(7b),R^(7c), R^(8a), R^(8b), R^(8c), R^(9a), R^(9b), R^(9c), R^(10a),R^(10b), and R^(10c) are as described above.

In one embodiment, the compound has the structure of one of Formulae(IVa), (IIIb) or (IVb). In one embodiment, the compound has thestructure of Formula (IVa). In one embodiment, the compound has thestructure of Formula (IIIb). In one embodiment, the compound has thestructure of Formula (IVb).

In one embodiment of the methods provided herein, the compound isprovided within a pharmaceutical composition such as a solution,emulsion, gel or foam. In one embodiment, the pharmaceutical compositionis a solution. In one embodiment, the composition is an emulsion. In oneembodiment, the composition is a gel. In one embodiment, the compositionis a foam.

It is understood that the compounds useful in the methods providedherein (e.g., a compound with structure of Formula (I), (II), (III),(IV), (IIa), (IIb), (IIc), (IIIa), (IIIb), (IIIc), (IIId), (IVa), (IVb),or (IVc) or derivative, isomer or enantiomer thereof and includingembodiments thereof) can be provided, where applicable, as apharmaceutically acceptable salt as defined herein, where the compoundadmits to formation of a pharmaceutically acceptable salt.

V. Examples

The examples below are meant to illustrate certain embodiments of theinvention, and not to limit the scope of the invention. Startingmaterials for syntheses described herein are commercially available orcan be synthesized by methods known in the art and/or described herein.

Example 1 Synthesis of 11 propionyl bimatoprost Example 1a Synthesis of15-tert-butyldimethylsilyloxy-bimatoprost

A solution of bimatoprost (270 mg; 0.65 mmoles) and n-butylboronic acid(83 mg; 0.81 mmoles) in anhydrous dichloromethane (2 ml) was stirred toreflux for 40 minutes, cooled, evaporated in vacuo and azeotroped withanhydrous benzene (3×5 ml). To the residue was added anhydrousdichloromethane (2.5 ml) then, over an ice bath, 2,6-lutidine (0.20 ml;1.7 mmoles) and tert-butyldimethylsilyl trifluoromethanesulfonate (340mg; 1.3 mmoles) were added. The resulting mixture was stirred overnightat ambient temperature then partitioned between ethyl acetate and 10%aqueous citric acid. The organic layer was separated, washed with brine,dried over sodium sulfate and evaporated in vacuo. The residue wasstirred in methanol (6 ml) for 2 hours and evaporated in vacuo.15-tert-butyldimethylsilyloxy-bimatoprost (220 mg; 64%) was obtained asa clear oil following silica gel chromatography of the residue elutingwith 50-100% ethyl acetate in hexanes.

Example 1b Synthesis of Synthesis of15-tert-butyldimethylsilyloxy-11-propionyl-bimatoprost

To a solution of 15-tert-butyldimethylsilyloxy-bimatoprost (100 mg; 0.19mmoles) in anhydrous pyridine (1 ml) was added propionyl chloride (20μL; 0.23 mmoles) at 0° C. The mixture was left at 4° C. for 16 hours,then partitioned between ethyl acetate and 10% aqueous citric acid. Theorganic layer was separated, washed with brine, dried over sodiumsulfate and evaporated in vacuo.15-tert-butyldimethylsilyloxy-11-propionyl-bimatoprost (55 mg; 50%) wasobtained as a clear oil following silica gel chromatography of theresidue eluting with 40-60% ethyl acetate in hexanes.

Example 1c Synthesis of 11-propionyl bimatoprost (IIIb)

To a solution of 15-tert-butyldimethylsilyloxy-11-propionyl-bimatoprost(60 mg; 1.02 mmoles) in a mixture of acetonitrile (1.5 ml) andtetrahydrofuran (1 ml) at 0° C. was added aqueous hydrofluoric acid(48-51%; 0.1 ml). The solution was warmed to room temperature. After 30minutes, water (5 ml) was added and the mixture extracted withdichloromethane (2×10 ml). The combined organic layers were dried oversodium sulfate and evaporated in vacuo. 11-propionyl bimatoprost (43 mg;89%) was obtained as a clear oil following silica gel chromatography ofthe residue eluting with 50-100% ethyl acetate in hexanes.

Example 2 Synthesis of 11-butyryl-bimatoprost Example 2a Synthesis of15-tert-butyldimethylsilyloxy-11-butyryl-bimatoprost

Compound 15-tert-butyldimethylsilyloxy-11-butyryl-bimatoprost (41 mg;36%) was synthesized as a clear oil from15-tert-butyldimethylsilyloxy-bimatoprost (100 mg; 0.19 mmoles) andbutyryl chloride (24 μL; 0.23 mmoles) in an analogous manner to thatdescribed in Example 1.b.

Example 2b Synthesis of 11-butyryl-bimatoprost (IIIc)

Compound 11-butyryl-bimatoprost (30 mg; 91%) was synthesized as a paleoil from 15-tert-butyldimethylsilyloxy-11-butyryl-bimatoprost (41 mg;0.068 mmoles) in an analogous manner to that described in Example 1c.

Example 3 Synthesis of 15-propionyl-bimatoprost (IVb)

A solution of bimatoprost (90 mg; 0.22 mmoles) and n-butylboronic acid(28 mg; 0.27 mmoles) in anhydrous dichloromethane (1 ml) was stirred toreflux for 40 minutes, cooled, evaporated in vacuo and azeotroped withanhydrous benzene (3×2 ml). To the residue was added anhydrousdichloromethane (1 ml) then, over an ice bath, triethylamine (0.11 ml;0.79 mmoles), 4-dimethylaminopyridine (15 mg; 0.12 mmoles) and propionicanhydride (42 μl; 0.33 mmoles) were added. The resulting mixture wasstirred overnight at ambient temperature then partitioned between ethylacetate and 10% aqueous citric acid. The organic layer was separated,washed with brine, dried over sodium sulfate and evaporated in vacuo.The residue was stirred in methanol (2 ml) for 2 hours and evaporated invacuo. Compound 15-propionyl bimatoprost (90 mg; 88%) was obtained as aclear oil following silica gel chromatography of the residue elutingwith a gradient of 50% ethyl acetate in hexanes to 5% methanol in ethylacetate.

Example 4 Synthesis of 15-butyryl bimatoprost (IVc)

Compound 15-butyryl bimatoprost (63 mg; 59%) was synthesized as a clearoil from bimatoprost (90 mg; 0.22 mmoles) and butyric anhydride (53 μL;0.32 mmoles) in an analogous manner to that described in Example 3.

Example 5 Synthesis of 9-isobutyryl-bimatoprost Example 5a Synthesis of11,15-di-tert-butyldimethylsilyloxy-bimatoprost

To a solution of bimatoprost (50 mg; 0.12 mmoles) and imidazole (33 mg;0.48 mmoles) in anhydrous N,N-dimethylformamide (0.25 ml) was addedtert-butyldimethylsilyl chloride (37 mg; 0.24 mmoles). The mixture wasstirred overnight at ambient temperature then partitioned between ethylacetate and 10% aqueous citric acid. The organic layer was separated,washed with brine, dried over sodium sulfate and evaporated in vacuo toyield 11,15-di-tert-butyldimethylsilyloxy-bimatoprost.

Example 5b Synthesis of11,15-di-tert-butyldimethylsilyloxy-9-isobutyryl-bimatoprost

To a solution of 11,15-di-tert-butyldimethylsilyloxy-bimatoprost (133mg; 0.21 mmoles) in anhydrous pyridine (0.41 ml) was added isobutyrylchloride (44 μL; 0.42 mmoles) at 0° C. The mixture was allowed to warmgradually to ambient temperature and stirred for 16 hours, thenevaporated in vacuo. Compound11,15-di-tert-butyldimethylsilyloxy-9-isobutyryl-bimatoprost (145 mg;99%) was obtained following silica gel chromatography of the residueeluting with 50% ethyl acetate in hexanes.

Example 5c Synthesis of 9-isobutyryl-bimatoprost (IIc)

To a solution of11,15-di-tert-butyldimethylsilyloxy-9-isobutyryl-bimatoprost (145 mg;0.20 mmoles) in tetrahydrofuran (0.25 ml) was added tetrabutylammoniumfluoride (1M in THF; 0.2 ml). After 6 hours the reaction mixture wasevaporated in vacuo. Compound 9-isobutyryl-bimatoprost (48 mg; 49%) wasobtained following silica gel chromatography of the residue eluting withethyl acetate.

Example 6 Synthesis of 15-acetyl-bimatoprost (IVa)

A solution of bimatoprost (180 mg; 0.43 mmoles) and n-butylboronic acid(53 mg; 0.52 mmoles) in anhydrous dichloromethane (1 ml) was stirred toreflux for 4 hours, cooled and evaporated in vacuo. To the residue wasadded anhydrous pyridine (0.9 ml) then, at 0° C., acetyl chloride (0.05ml; 0.70 mmoles). The reaction mixture was stirred for 3 hours thenpartitioned between ethyl acetate and 10% aqueous citric acid. Theorganic layer was separated, washed with brine, dried over sodiumsulfate and evaporated in vacuo. The residue was stirred in methanol (5ml) for 4 hours and evaporated in vacuo. Compound 15-acetyl-bimatoprost(150 mg; 76%) was obtained following silica gel chromatography of theresidue eluting with 10% methanol in dichloromethane.

Example 7 Formulation and Stability Studies

Experimental Design.

Stability over time of compounds disclosed herein was determined informulation as a function of temperature and pH. Variations ofFormulation A described herein were employed wherein the targetconcentration of active agent was 0.03%, and the pH was varied at pH 4,5, 6 and 7. Temperatures of 25° C., 40° C. and 60° C. were maintainedduring the experiment. Samples were evaluated at zero time and 80-days.

Compounds.

Cmpds IVa, IIIb, and IVb for evaluated for stability.

Results.

FIGS. 1A-1B, 2A-2B, and 3A-3B depict histograms of relativeconcentrations of test compounds (arbitrary scale) at zero time or80-days. FIG. 1A depicts a histogram of the stability profile of CmpdIVa as a function of pH and temperature. FIG. 1B depicts a histogram ofthe formation of bimatoprost as a function of pH and temperature after80-days for Cmpd IVa. FIG. 2A depicts a histogram of the stabilityprofile of Cmpd IVb as a function of pH and temperature. FIG. 2B depictsa histogram of the formation of bimatoprost as a function of pH andtemperature after 80-days for Cmpd IVb. FIG. 3A depicts a histogram ofthe stability profile of Cmpd IIIb as a function of pH and temperature.FIG. 3B depicts a histogram of the formation of bimatoprost as afunction of pH and temperature after 80-days for Cmpd IIIb.

Conclusion.

These studies disclose that compounds described herein, as exemplifiedby Cmpds IVa, IIIb, and IVb are stable in formulation.

Example 8 In Vitro Dermal Irritation Studies

Experimental Design.

In vitro irritation screening assays were conducted for compoundsdescribed herein. Test system was the reconstructed human epidermis(RHE), as known in the art. Single dosing was employed, and endpointswere evaluated as a function of time up to 24-hrs. Endpoints were tissueviability and IL-1α release.

Test Compounds.

Test compounds included Cmpds IVa (0.03%), IIIb (0.03%), IVb (0.03%),bimatoprost (0.03%), minoxidil (5%, foam), and minoxidil (5%, solution).Administration of Cmpds IVa, IIIb, IVb and bimatoprost employed thevehicle of Formulation A. See Table 1 above. Administration of minoxidilemployed minoxidil vehicle with formulation 20% H₂O, 50% propyleneglycol, and 30% ethanol.

Results.

In the RHE system, no significant decreases in tissue viability wereobserved for any of the tested compounds up to 24-hrs. Similarly, nosignificant increase in IL-1α release was observed during this time.

Conclusion.

Cmpds IVa, IIIb, and IVb showed no indication of potential forirritation of the human skin at concentration 0.03%. Irritationpotential is comparable to commercially available formulations ofminoxidil, as known in the art.

Example 9 Dermal Tolerability in Rats

Experimental Design.

Female rats were administered either vehicle or one of Cmpds IVa, IIIb,or IVb daily for 8 days. The administered dose was 3 mg/kg/day, at aconcentration of 3 mg/mL. Observed data were body weight, viability,food consumption, and dermal observation (skin reaction grading), asknown in the art. The vehicle was Formulation A. See Table 1 above.

Results.

No morbidity or unscheduled death of a test animal was observed.Moreover, there was no observed clinical signs of toxicity. Regardingdermal observations, there was no observation of edema. There wasminimal and transient signs of irritation at days 2-4 for Cmpds IVa andIIIb.

Regarding food consumption and body weight changes, as provided in Table4 following, for Cmpds IVa and IIIb no significant change in foodconsumption or body weight gain was observed during the experiment.Although not statistically significant, decreases in both foodconsumption and body weight gain were observed for Cmpd IVb. Withoutwishing to be bound by any theory, it is believed that the decrease infood consumption and body weight for Cmpd IVb was due to decreases in asubset of the tested animals (i.e., 2 of 3 demonstrated decreases infood consumption and body weight.

TABLE 4 Food Consumption and Body Weight Studies Vehicle Cmpd IVa CmpdIIIb Cmpd IVb Food Consumption (g) Mean ± SD 21.95 ± 1.66 21.14 ± 1.08 22.8 ± 1.36 19.19 ± 1.32 Body Weight Gain (g) Mean ± SD  8.0 ± 3.0 9.0 ±3.0 10.0 ± 6.1   0.3 ± 6.7

Example 10 Mutagenesis Studies

Experimental Design.

Cmpds IVa, IIIb, and IVb were subjected to the microAmes screen, asknown in the art.

Results.

Cmpds IVa, IIIb, and IVb were judged to be not mutagenic, with orwithout metabolic activation, under the conditions of the microAmesscreen.

Example 11 Cellular Dielectric Spectroscopy Studies

Experimental Design.

Cellular dielectric spectroscopy (CDS) was conducted in an assay ofdermal papilla cells (i.e., human hair dermal papilla cells, HHDPC) withbimatoprost and Cmpds IVc and IVb. As known in the art, CDS is areal-time, non-invasive, label-free, high-throughput, cell-based assaywhich measures electrical cell impedance. Without wishing to be bound byany theory, it is believed that GPCR activation induces changes in cellmorphology, cell-cell interaction, and cell adherence which manifest asa change in cell impedance.

Results.

Functional studies of bimatoprost, Cmpd IVc and Cmpd IVb to HHDPC wereconducted. For bimatoprost, submicromolar activity was observed, asjudged by EC₅₀ values in the range 3.0 to 6.3×10⁻⁷ mol/L. In contrast,EC₅₀ could not be determined for Cmpds IVc and IVb in the range of 10⁻⁴to 10⁻¹³ mol/L. As understood in the art, the term “EC₅₀” refers to theeffective concentration at 50% of maximum activity.

Moreover, bimatoprost interacts with HHDPC to provide a characteristicchange in cell impedance which is understood to correlate with receptorbinding. In contrast, Cmpds IVc and IVb were not observed to provide achange in cell impedance under the conditions of the assay.

Conclusion.

Without wishing to be bound by any theory, it is believed that compoundsdisclosed herein (e.g., Cmpds IVc and IVb) do not activate HHDPC. Incontrast, bimatoprost activates HHDPC. Accordingly, compounds describedherein which undergo hydrolysis can afford bimatoprost, which can thenactivate HHDPC.

Example 12 Piliation Studies

Experimental Design.

C57Black/6J, 7-week old female mice (n=10) were employed in piliationstudies. Dorsal hair was shaved (area ˜2 cm×4 cm). Dosing of activeagent was once per day (QD) by topical administration for 14 days.Observations were conducted for 42-days to determine onset of new hairgrowth and day of hair growth completion. Compounds were formulated aseither a) 50% propylene glycol, 30% ethanol, 20% water, or b) theformulation of Formulation A described above. The experiments reportedfor FIGS. 4A-4B, 5A-5B, 6A-6B, 8A-8B, and 9A-9B were conducted using avehicle with formulation of 50% propylene glycol, 30% ethanol, 20%water. The experiments reported for FIGS. 7A-7B were conducted using avehicle of Formulation A described above.

Results.

For each of FIGS. 4A, 5A, 6A, 7A, 8A and 9A, the histograms depict theday of onset of hair growth. For each of FIGS. 4B, 5B, 6B, 7B, 8B and9B, the histograms depict the day achieving full hair growth. In thesefigures, an entry of “70” indicates that full hair growth was notobserved at the end of the study (i.e., day 42).

FIG. 4A depicts a histogram of the day of onset of hair growth, and FIG.4B depicts the day of full hair growth for (A) vehicle; (B) 0.03%bimatoprost; (C) 0.03% Cmpd IIc; (D) 0.03% Cmpd IIa; and (E) 0.03% CmpdIIIa.

FIG. 5A depicts a histogram of the day of onset of hair growth, and FIG.5B depicts the day of full hair growth for (A) vehicle; (B) 0.03%bimatoprost; (C) 0.03% Cmpd IIId; and (D) 0.03% Cmpd IVa.

FIG. 6A depicts a histogram of the day of onset of hair growth, and FIG.6B depicts the day of full hair growth for (A) vehicle; (B) 0.03%bimatoprost; (C) 0.03% Cmpd IIIb; (D) 0.03% Cmpd IIIb; (E) 0.03% CmpdIVc; and (F) 0.03% Cmpd IIIc.

FIG. 7A depicts a histogram of the day of onset of hair growth, and FIG.7B depicts the day of full hair growth for (A) vehicle (Formulation A);(B) 0.03% bimatoprost; (C) 0.03% Cmpd IVa; (D) 0.03% Cmpd IIIb; and (E)0.03% Cmpd IVb.

FIG. 8A depicts a histogram of the day of onset of hair growth, and FIG.8B depicts the day of full hair growth for (A) vehicle; (B) 0.03%bimatoprost; (C) 0.03% Cmpd IIIb; and (D) 0.03% Cmpd IVb.

FIG. 9A depicts a histogram of the day of onset of hair growth, and FIG.9B depicts the day of full hair growth for (A) vehicle; (B) 0.3%bimatoprost; (C) 0.1% bimatoprost; (D) 0.03% bimatoprost; and (E) 0.03%Cmpd IVa.

Conclusion.

Compounds disclosed herein were tested for the ability to induce hairgrowth. The 15-proprionyl bimatoprost Cmpd IVb appeared to have the bestactivity in the time required to regain full hair growth. It is notedthat 0.03% bimatoprost is the same active agent which is found in themarketed hair growth product LATISSE®. With reference to FIG. 6A, while0.03% bimatoprost took 22 days to for hair growth to commence,15-proprionyl bimatoprost Cmpd IVb took only 16 days for hair growth tocommence. And, while 0.03% bimatoprost took 44 days for full hair growthto be achieved, 15-proprionyl bimatoprost Cmpd IVb took only 32 days forfull hair growth to be achieved.

Accordingly, Cmpd IVa demonstrates pharmacological efficacy greater thanbimatoprost in the mouse model of hair regrowth using a vehicleformulation of 50% propylene glycol, 30% ethanol, 20% water. Moreover,Cmpd IVa demonstrates pharmacological efficacy greater than bimatoprostin this model using a vehicle formulation of Formulation A. Withinstatistical significance limits, Cmpds IIIb and IVb provideapproximately equivalent efficacy in this model with respect tobimatoprost using a vehicle formulation of Formulation A.

Moreover, as surprisingly demonstrated in FIGS. 7A-7B, compared to 0.1%to 0.3% bimatoprost, 0.03% Cmpd IVa is approximately equally effective.Accordingly, without wishing to be bound by any theory, it is believedthat the use of lower concentrations of Cmpd IVa, relative tobimatoprost. is indicated for equivalent effectiveness.

Example 13 Pathology Assessment of Mouse Hair Regrowth Model

Experimental Design.

Histological samples from test subjects employed in the studiesdescribed in Example 12 were obtained for pathology assessment.

Results.

As shown in FIGS. 10A-10E, for vehicle, bimatoprost, Cmpd IVa, Cmpd IIIband Cmpd IV, respectively, the hair cycle of mice treated with activeagent had returned to the resting phase at day-42 while the vehiclecontrol was still in growth phase. No adverse effects were observed atday-42 in the mouse skin.

Example 14 Pharmacokinetic Assessment of Mouse Hair Regrowth Model

Experimental Design.

Female C57BL/6J mice (n=2) were assayed per time point per treatmentgroup. Treatment groups: (1) vehicle; (2) 0.03% Cmpd IVa; (3) 0.03% CmpdIIIb; (4) 0.03% Cmpd IVb; (5) 0.03% bimatoprost. Treatment dosing:dermal daily application of ˜60 uL test compound solution. Blood andskin pharmacokinetic time points were obtained at day 1 (1, 4, 8 and24-hrs post-dose); day 2 (24-hrs post-dose); day 14 (24-hrs post-dose);and day 42 (28 days post day 14 dose). Bioanalysis employed LC/MS-MS.

Results.

FIG. 11A depicts mean concentration of bimatoprost and Cmpds IVa, IIIband IVb in the skin. FIG. 11B depicts mean concentration of bimatoprostat the equivalent time points. Bimatoprost, and Cmpds IVa, IIIb and IVbwere most undetectable in the systemic circulation at all measured timepoints.

Conclusion.

The mean bimatoprost skin concentrations observed from conversion ofCmpds IVa, IIIb and IVb were >75% lower than the level observed in thebimatoprost treatment group. See FIG. 11B. Without wishing to be boundby any theory, it is believed that enhanced efficacy of Cmpds IVa, IIIband IVb may be due, at least in part, to targeted distribution to hairfollicles.

Example 15 Studies on Formation of Bimatoprost from Prodrug

Experimental Design.

The rate of formation of bimatoprost from Cmpd IVa and Cmpd IVb wasdetermined in human cadaver skin.

Results.

As shown in FIG. 12, both Cmpd IVa and Cmpd IVb afford bimatoprost whenincubated with human cadaver skin. Rate of formation: Cmpd IVa (1.32pmol/min/mg); Cmpd IVb (5.59 pmol/min/mg).

Example 16 In Vitro Human Skin Penetration Studies

Experimental Design.

Test material: Dermatomed ex vivo human cadaver posterior trunk skin on1.0 cm² Franz diffusion chamber as known in the art. Test size: 3 skindonors (40 year old African American, 60 year old Caucasian, 72 year oldCaucasian, obtained from New York Firefighters Skin Bank), 3 replicatesper donor per formulation. Test formulations: 0.03% active agent (CmpdIVa, Cmpd IIIb, Cmpd IVb) in Formulation A; control formulation:bimatoprost at 0.03% in Formulation A. Dosing regimen: receptor fluid at2, 4, 24, and 48 hrs; SC/epidermis and dermis at 48 hrs. Sampleanalysis: LC/MS-MS to detect bimatoprost and Cmpds IVa, IIIb and IVb.

Results: Skin Penetration.

As shown in FIG. 13A, each active agent penetrated the skin during thecourse of the experiment. The penetration of Cmpds IVa, IIIb and IVb wassignificantly greater than for bimatoprost. As shown in FIG. 13B, thepenetration flux for Cmpds IVa, IIIb and IVb was greater than that forbimatoprost.

Results: Conversion to Bimatoprost in Receptor Chamber Solution.

Each of Cmpds IVa, IIIb and IVb was observed to convert to bimatoprostin the receptor chamber solution, as evidenced in FIGS. 14A-14C, whichare histograms of cumulative concentration of compounds in receptorchamber solution.

Results: Skin Distribution and Conversion to Bimatoprost.

As shown in FIG. 15A, the total amount of any of Cmpds IVa, IIIb and IVbdistributed into skin layers is similar to that observed forbimatoprost. Moreover, Cmpds IVa, IIIb and IVb are converted tobimatoprost in the SC/Epi/Dermis layers. FIG. 15B depicts a histogram ofskin retention per agent in the dermis. It is observed that the amountof active agent (Cmpds IVa, IIIb and IVb) in the upper third of thedermis is less than observed for bimatoprost.

In summary, as shown in Table 5 following, the percentage of the doseapplied for prodrug (i.e., Cmpds IVa, IIIb or IVb) and bimatoprost(i.e., either applied or resulting from metabolism of the prodrug),evidences appearance of bimatoprost in the receptor chamber solution andthe upper third of the dermis. “N.A.” refers to “not available.”

TABLE 5 Percentage Dose Applied of Agent. Receptor Chamber SolutionUpper ⅓ Dermis Agent Prodrug Metabolite Total Prodrug Metabolite TotalBimatoprost 1.1 N.A 1.1 7.0 N.A. 7.0 Cmpd IVa 4.3 2.3 6.6 3.8 0.9 4.7Cmpd IIIb 0.8 7.8 8.5 2.1 1.0 3.0 Cmpd IVb 2.1 5.0 7.1 1.9 0.5 2.4

Conclusions.

Surprisingly, Cmpds IVa, IIIb and IVb are more permeable thanbimatoprost, with increased bimatoprost concentration in the receptorchamber solution. Cmpds IVa, IIIb and IVb are distributed intoSC/Epidermis/Upper dermis to the same extent as bimatoprost, but theseactive agents demonstrate less retention than bimatoprost in the upperthird of the dermis.

Example 17 Partitioning in Artificial Sebum

Rationale.

Without wishing to be bound by any theory, it is believed that ifbimatoprost and prodrugs thereof were to penetrate the skin through thesemi-liquid sebum phase to the hair follicle, then prodrugs havingsebum-water partitioning greater than bimatoprost may achieve greaterhair growth efficacy than observed with bimatoprost.

Experimental Design.

Compounds bimatoprost, Cmpd IVa, and Cmpd IIIb were added to aqueoussolution (1 mL, 2-20 ug/mL), with and without 1-20 mg artificial sebum.Samples were shaken for 16 hr at 37° C. Samples were then centrifuged(8000 RPM) for 15 min at room temperature, prior to collection of theaqueous solution. Samples were analyzed for concentration of compoundwithout artificial sebum (i.e., C_(o)) and with artificial sebum (i.e.,C_(i)) by mass spectroscopy. Artificial sebum and water partitioncoefficient (K_(sebum)) was expressed as the concentration of drug in 1g of artificial sebum divided by the concentration of drug in 1 g ofaqueous solution, and was calculated asK_(sebum)=(C_(o)−C_(i))W_(aqueous)/(C_(i)×W_(sebum)) (Eqn. 1), where Wrepresents weight.

Artificial Sebum.

Artificial sebum was prepared as follows: 15% (w/w) squalene, 15%spermaceti, 10% coconut oil, 1.5% oleic acid, 5% palmitic acid, 2.4%cholesterol oleate, 10% paraffin wax, 10% olive oil, 25% cottonseed oil,5% palmitoleic acid, 1.2% cholesterol. The melting point of thesemi-liquid was 37° C.

Results.

As shown in Table 6 following for n=4 trials, under the experimentalconditions, K_(sebum) is observed to correlate with LogP, calculated bymethods well known in the art. Specifically, without wishing to be boundby any theory, it is observed that the more lipophilic a compound, themore partitioning is observed into artificial sebum. Moreover, it isobserved that the majority of bimatoprost and Cmpds IVa and IIIb remainin the aqueous phase.

TABLE 6 Results of Partitioning in Artificial Sebum for SelectedCompounds n = 4 bimatoprost Cmpd IVa Cmpd IIIb LogP 1.98 2.90 3.64 Ave.K_(sebum) 3.6 5.1 6.1

Example 18 Compound Distribution in Mouse Skin

Rationale.

In order to determine the penetration, accumulation and/or differentialdistribution of bimatoprost and compounds disclosed herein upon dermaladministration, MALDI-MS (matrix assisted laser desorption ionizationmass spectroscopy) imaging was conducted on explanted samples of mouseskin after topical dermal administration.

Experimental Design.

MALDI-MS imaging was conducted on mouse skin strips after administrationof bimatoprost or compound disclosed herein once daily for 3 days.Samples of mouse skin were recovered 4 hr after day-3 dosing ofcompound. Dermal administration was conducted with vehicle, 0.03%bimatoprost, 3% bimatoprost, 0.03% Cmpd IVa, and 3% Cmpd IVa.

FIG. 16A depicts a typical explanted sample of mouse skin for thesestudies, wherein Cmpd IVa was applied via dermal administration. FIG.16B depicts the result of MALDI-MS imaging. The intensity of each pixelwithin FIG. 16B reflects the concentration of Cmpd IVa at thecorresponding point in the image depicted in FIG. 16A. FIG. 16C depictsa representative mass spectrum, corresponding to the region of FIG. 16Bindicated by the white circle within FIG. 16B. Accordingly, each pixelof the image of FIG. 16B has an associated mass spectrum, providing theamounts of bimatoprost or other administered compound or metabolitethereof.

Results.

MALDI-MS imaging is able to selectively detect Cmpd IVa and bimatoprostfollowing topical dermal administration of 3.0% Cmpd IVa on mouse skin.Without wishing to be bound by any theory, it is believed that MALDI-MSimaging has sufficient sensitivity to detect bimatoprost and compoundsdisclosed herein upon topical dermal administration at 3% (w/w) dosage,or even greater sensitivity. Indeed, Cmpd IVa was detectable in theassay system after administration of Cmpd IVa at 0.03%, whereas vehiclecontrol samples displayed no signal for Cmpd IVa.

Moreover, it was observed that the levels of bimatoprost in skin weremuch higher following topical dermal administration of 3.0% bimatoprostthan observed following topical dermal administration of 3.0% Cmpd IVa.

It was further observed that levels of bimatoprost are lower (i.e., onthe order 10× lower) following topical dermal administration of Cmpd IVacompared with administration of bimatoprost.

Without further wishing to be bound by any theory, it is observed thatskin penetration of bimatoprost after topical dermal administration of3.0% bimatoprost appears to be similar to the skin penetration of CmpdIVa after topical dermal administration of 3.0% Cmpd IVa.

What is claimed is:
 1. A compound with structure of Formula (I):

or derivative, isomer, or enantiomer thereof; wherein R¹ is hydrogen orR^(1a)C(O)—; R² is hydrogen or R^(2a)C(O)—; R³ is hydrogen orR^(3a)C(O)—; R^(1a), R^(2a) and R^(3a) are independently substituted orunsubstituted C₁-C₁₀ alkyl, substituted or unsubstituted C₃-C₈cycloalkyl, or substituted or unsubstituted aryl; and R⁴ and R⁵ areindependently hydrogen, substituted or unsubstituted C₁-C₁₀ alkyl, orsubstituted or unsubstituted C₃-C₈ cycloalkyl; provided, however, thatat least one of R¹, R² and R³ is not hydrogen.
 2. The compound of claim1, wherein R^(1a), R^(2a) and R^(3a) are independently substituted orunsubstituted C₁-C₆ alkyl.
 3. The compound of claim 2, wherein R^(1a),R^(2a) and R^(3a) are independently substituted or unsubstituted C₁-C₃alkyl.
 4. The compound of claim 3, wherein R^(1a), R^(2a) and R^(3a) areindependently substituted or unsubstituted C₁ alkyl.
 5. The compound ofclaim 4, wherein R^(1a), R^(2a) and R^(3a) are independently methyl. 6.The compound of claim 1, wherein R^(1a), R^(2a) and R^(3a) areindependently substituted or unsubstituted C₃-C₈ cycloalkyl.
 7. Thecompound of claim 6, wherein R^(1a), R^(2a) and R^(3a) are independentlyunsubstituted C₃-C₈ cycloalkyl.
 8. The compound of claim 1, whereinR^(1a), R^(2a) and R^(3a) are independently substituted or unsubstitutedaryl.
 9. The compound of claim 8, wherein R^(1a), R^(2a) and R^(3a) areindependently aryl.
 10. The compound of claim 1, wherein R^(1a), R^(2a)and R^(3a) are independently phenyl.
 11. The compound of claim 1,wherein R⁴ is substituted or unsubstituted C₁-C₁₀ alkyl, or substitutedor unsubstituted C₃-C₈ cycloalkyl.
 12. The compound of claim 11, whereinR⁴ is substituted or unsubstituted C₁-C₆ alkyl.
 13. The compound ofclaim 12, wherein R⁴ is substituted or unsubstituted C₁-C₃ alkyl. 14.The compound of claim 13, wherein R⁴ is substituted or unsubstituted C₂alkyl.
 15. The compound of claim 14, wherein R⁴ is ethyl.
 16. Thecompound of claim 11, wherein R⁴ is substituted or unsubstituted C₃-C₈cycloalkyl.
 17. The compound of claim 1, wherein R⁵ is hydrogen.
 18. Thecompound of claim 1, having the structure of Formula (IVa):


19. The compound of claim 1, having the structure of Formula (IIIb):


20. The compound of claim 1, having the structure of Formula (IVb):


21. A method for inducing hair growth in a human comprisingadministering to a subject in need thereof a therapeutically effectiveamount of a compound with structure of Formula (I):

or derivative, isomer, or enantiomer thereof; wherein R¹ is hydrogen orR^(1a)C(O)—; R² is hydrogen or R^(2a)C(O)—; R³ is hydrogen orR^(3a)C(O)—; R^(1a), R^(2a) and R^(3a) are independently substituted orunsubstituted C₁-C₁₀ alkyl, substituted or unsubstituted C₃-C₈cycloalkyl, or substituted or unsubstituted aryl; and R⁴ and R⁵ areindependently hydrogen, substituted or unsubstituted C₁-C₁₀ alkyl, orsubstituted or unsubstituted C₃-C₈ cycloalkyl; provided, however, thatat least one of R¹, R² and R³ is not hydrogen; thereby inducing hairgrowth.
 22. The method of claim 21, wherein said subject suffers fromalopecia.
 23. The method of claim 21, wherein said subject is in need ofhair growth of the cilia, the supercilia, scalp pili, or body pili. 24.The method of claim 21, wherein said administering is topicaladministering.
 25. The method of claim 24, wherein said administering istopical epidermal administering.
 26. The method of claim 21, whereinsaid compound is